Updated on 2025/08/22

写真a

 
HONMOU Osamu
 
Organization
Institute of Regenerative Medicine Department of Neural Regenerative Medicine Professor
Title
Professor
External link

Degree

  • Ph.D.

Research Interests

  • 神経再生

  • 移植治療

  • 脳神経外科学

Research Areas

  • Life Science / Neuroscience-general

Education

  • Sapporo Medical University

    - 1989

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    Country： Japan

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  • Sapporo Medical University

    - 1989

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Professional Memberships

Papers

  • Intravenous infusion of auto-serum-expanded autologous mesenchymal stem cells into chronic severe brain injury patients

    Tomohiro Yamaki, Shinichi Oka, Satoshi Iyama, Masanori Sasaki, Rie Onodera, Yuko Kataoka-Sasaki, Takahiro Namioka, Ai Namioka, Masahito Nakazaki, Mitsuhiro Takemura, Ryo Ukai, Takahiro Yokoyama, Yuichi Sasaki, Tatsuro Yamashita, Masato Kobayashi, Misako Yamaguchi, Marina Fukino, Taro Takazawa, Megumi Hayasaka, Takamitsu Owaku, Mika Funakura, Shinji Onodera, Yoichi M. Ito, Masayoshi Kobune, Junji Kato, Sumio Ishiai, Jeffery D. Kocsis, Masaru Odaki, Yasuo Iwadate, Shigeki Kobayashi, Osamu Honmou

    Interdisciplinary Neurosurgery: Advanced Techniques and Case Management   36   2024.6

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.inat.2023.101927

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  • 最新基礎科学/知っておきたい 骨髄間葉系幹細胞を用いた脊髄損傷治療の基礎と臨床

    廣田 亮介, 佐々木 祐典, 本望 修, 山下 敏彦

    臨床整形外科   59 ( 3 )   308 - 311   2024.3

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    Publisher：株式会社医学書院  

    DOI： 10.11477/mf.1408202924

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  • 頭部外傷後遺症に対する骨髄間葉系幹細胞投与後アミノ酸PETによる脳代謝変化の描出

    八巻 智洋, 岡 真一, 岡 信男, 佐々木 祐典, 本望 修, 小林 繁樹

    核医学   61 ( Suppl. )   S153 - S153   2024

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    Language：Japanese   Publisher：(一社)日本核医学会  

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  • Repeated intravenous infusion of mesenchymal stem cells enhances recovery of motor function in a rat model with chronic spinal cord injury. International journal

    Kota Kurihara, Masanori Sasaki, Hiroshi Nagahama, Hisashi Obara, Ryunosuke Fukushi, Ryosuke Hirota, Mitsunori Yoshimoto, Atsushi Teramoto, Jeffery D Kocsis, Toshihiko Yamashita, Osamu Honmou

    Brain research   1817   148484 - 148484   2023.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    Spinal cord injury (SCI) can cause paralysis with a high disease burden with limited treatment options. A single intravenous infusion of mesenchymal stem cells (MSCs) improves motor function in rat SCI models, possibly through the induction of axonal sprouting and remyelination. Repeated infusions (thrice at weekly intervals) of MSCs were administered to rats with chronic SCI to determine if multiple-dosing regimens enhance motor improvement. Chronic SCI rats were randomized and infused with vehicle (vehicle), single MSC injection at week 6 (MSC-1) or repeatedly injections of MSCs at 6, 7, and 8 weeks (MSC-3) after SCI induction. In addition, a single high dose of MSCs (HD-MSC) equivalent to thrice the single dose was infused at week 6. Locomotor function, light and electron microscopy, immunohistochemistry and ex vivo diffusion tensor imaging were performed. Repeated infusion of MSCs (MSC-3) provided the greatest functional recovery compared to single and single high-dose infusions. The density of remyelinated axons in the injured spinal cord was the greatest in the MSC-3 group, followed by the MSC-1, HD-MSC and vehicle groups. Increased sprouting of the corticospinal tract and serotonergic axon density was the greatest in the MSC-3 group, followed by MSC-1, HD-MSC, and vehicle groups. Repeated infusion of MSCs over three weeks resulted in greater functional improvement than single administration of MSCs, even when the number of infused cells was tripled. MSC-treated rats showed axonal sprouting and remyelination in the chronic phase of SCI.

    DOI： 10.1016/j.brainres.2023.148484

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  • Therapeutic efficacy of intravenous infusion of mesenchymal stem cells in rat perinatal brain injury. International journal

    Kojiro Terada, Masanori Sasaki, Hiroshi Nagahama, Yuko Kataoka-Sasaki, Shinichi Oka, Ryo Ukai, Takahiro Yokoyama, Yusuke Iizuka, Takuro Sakai, Shinobu Fukumura, Takeshi Tsugawa, Jeffery D Kocsis, Osamu Honmou

    Pediatric research   2023.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Perinatal brain injury is multifactorial and primarily associated with brain prematurity, inflammation, and hypoxia-ischemia. Although recent advances in perinatal medicine have improved the survival rates of preterm infants, neurodevelopmental disorders remain a significant complication. We tested whether the intravenous infusion of mesenchymal stem cells (MSCs) had therapeutic efficacy against perinatal brain injury in rats. METHODS: Pregnant rats at embryonic day (E) 18 received lipopolysaccharide and the pups were born at E21. On postnatal day (PND) 7, the left common carotid artery of each pup was ligated, and they were exposed to 8% oxygen for 2 h. They were randomized on PND10, and MSCs or vehicle were intravenously infused. We performed behavioral assessments, measured brain volume using MRI, and performed histological analyses on PND49. RESULTS: Infused MSCs showed functional improvements in our model. In vivo MRI revealed that MSC infusion increased non-ischemic brain volume compared to the vehicle group. Histological analyses showed that cortical thickness, the number of NeuN+ and GAD67+ cells, and synaptophysin density in the non-ischemic hemisphere in the MSC group were greater than the vehicle group, but less than the control group. CONCLUSIONS: Infused MSCs improve sensorimotor and cognitive functions in perinatal brain injury and enhance neuronal growth. IMPACT: Intravenous infusion of MSCs improved neurological function in rats with perinatal brain injury, including motor, sensorimotor, cognitive, spatial, and learning memory. Infused MSCs increased residual (non-ischemic) tissue volume, number of neuronal cells, GABAergic cells, and cortical synapses in the contralesional (right) hemisphere. Intravenous administration of MSC might be suitable for the treatment of perinatal brain injury.

    DOI： 10.1038/s41390-023-02717-9

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  • Enhanced Network in Corticospinal Tracts after Infused Mesenchymal Stem Cells in Spinal Cord Injury. International journal

    Ryosuke Hirota, Masanori Sasaki, Yuko Kataoka-Sasaki, Tsutomu Oshigiri, Kota Kurihara, Ryunosuke Fukushi, Shinichi Oka, Ryo Ukai, Mitsunori Yoshimoto, Jeffery D Kocsis, Toshihiko Yamashita, Osamu Honmou

    Journal of neurotrauma   39 ( 23-24 )   1665 - 1677   2022.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    Although limited spontaneous recovery occurs after spinal cord injury (SCI), current knowledge reveals that multiple forms of axon growth in spared axons can lead to circuit reorganization and a detour or relay pathways. This hypothesis has been derived mainly from studies of the corticospinal tract (CST), which is the primary descending motor pathway in mammals. The major CST is the dorsal CST (dCST), being the major projection from cortex to spinal cord. Two other components often called "minor" pathways are the ventral and the dorsal lateral CSTs, which may play an important role in spontaneous recovery. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvement after SCI with an enhancement of axonal sprouting of CSTs. Detailed morphological changes of CST pathways, however, have not been fully elucidated. The primary objective was to evaluate detailed changes in descending CST projections in SCI after MSC infusion. The MSCs were infused intravenously one day after SCI. A combination of adeno-associated viral vector (AAV), which is an anterograde and non-transsynaptic axonal tracer, was injected 14 days after SCI induction. The AAV with advanced tissue clearing techniques were used to visualize the distribution pattern and high-resolution features of the individual axons coursing from above to below the lesion. The results demonstrated increased observable axonal connections between the dCST and axons in the lateral funiculus, both rostral and caudal to the lesion core, and an increase in observable axons in the dCST below the lesion. This increased axonal network could contribute to functional recovery by providing greater input to the spinal cord below the lesion.

    DOI： 10.1089/neu.2022.0106

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  • Repeated intravenous infusion of mesenchymal stem cells for enhanced functional recovery in a rat model of chronic cerebral ischemia. International journal

    Mitsuhiro Takemura, Masanori Sasaki, Yuko Kataoka-Sasaki, Ryo Kiyose, Hiroshi Nagahama, Shinichi Oka, Ryo Ukai, Takahiro Yokoyama, Jeffery D Kocsis, Tetsuya Ueba, Osamu Honmou

    Journal of neurosurgery   1 - 10   2021.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    OBJECTIVE: Stroke is a major cause of long-term disability, and there are few effective treatments that improve function in patients during the chronic phase of stroke. Previous research has shown that single systemic infusion of mesenchymal stem cells (MSCs) improves motor function in acute and chronic cerebral ischemia models in rats. A possible mechanism that could explain such an event includes the enhanced neural connections between cerebral hemispheres that contribute to therapeutic effects. In the present study, repeated infusions (3 times at weekly intervals) of MSCs were administered in a rat model of chronic stroke to determine if multiple dosing facilitated plasticity in neural connections. METHODS: The authors induced middle cerebral artery occlusion (MCAO) in rats and, 8 weeks thereafter, used them as a chronic stroke model. The rats with MCAO were randomized and intravenously infused with vehicle only (vehicle group); with MSCs at week 8 (single administration: MSC-1 group); or with MSCs at weeks 8, 9, and 10 (3 times, repeated administration: MSC-3 group) via femoral veins. Ischemic lesion volume and behavioral performance were examined. Fifteen weeks after induction of MCAO, the thickness of the corpus callosum (CC) was determined using Nissl staining. Immunohistochemical analysis of the CC was performed using anti-neurofilament antibody. Interhemispheric connections through the CC were assessed ex vivo by diffusion tensor imaging. RESULTS: Motor recovery was better in the MSC-3 group than in the MSC-1 group. In each group, there was no change in the ischemic volume before and after infusion. However, both thickness and optical density of neurofilament staining in the CC were greater in the MSC-3 group, followed by the MSC-1 group, and then the vehicle group. The increased thickness and optical density of neurofilament in the CC correlated with motor function at 15 weeks following induction of MCAO. Preserved neural tracts that ran through interhemispheric connections via the CC were also more extensive in the MSC-3 group, followed by the MSC-1 group and then the vehicle group, as observed ex vivo using diffusion tensor imaging. CONCLUSIONS: These results indicate that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. In addition, administration of MSCs is associated with promotion of interhemispheric connectivity through the CC in the chronic phase of cerebral infarction.

    DOI： 10.3171/2021.8.JNS21687

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  • MRIの基礎と応用技術 神経再生治療によって惹起される神経可塑性のMRIによる評価

    長濱 宏史, 佐々木 祐典, 清瀬 亮, 安田 尚美, 本望 修

    日本放射線技術学会雑誌   77 ( 10 )   1238 - 1244   2021.10

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  • Intravenous Infusion of Mesenchymal Stem Cells Promotes the Survival of Random Pattern Flaps in Rats

    Tsugufumi Nakagawa, Masanori Sasaki, Yuko Kataoka-Sasaki, Takatoshi Yotsuyanagi, Christine Radtke, Jeffery D. Kocsis, Osamu Honmou

    Plastic & Reconstructive Surgery   Publish Ahead of Print   2021.8

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    Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

    DOI： 10.1097/prs.0000000000008327

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  • Intravenous Infusion of Mesenchymal Stem Cells Enhances Therapeutic Efficacy of Reperfusion Therapy in Cerebral Ischemia. International journal

    Ryo Kiyose, Masanori Sasaki, Yuko Kataoka-Sasaki, Masahito Nakazaki, Hiroshi Nagahama, Hirotoshi Magota, Shinichi Oka, Ryo Ukai, Mitsuhiro Takemura, Takahiro Yokoyama, Jeffery D Kocsis, Osamu Honmou

    World neurosurgery   149   e160-e169   2021.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    OBJECTIVE: Reperfusion therapy is a standard therapeutic strategy for acute stroke. Non-favorable outcomes are thought to partially result from impaired microcirculatory flow in ischemic tissue. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in stroke. One suggested therapeutic mechanism is the restoration of the microvasculature. The goal of this study was to determine whether infused MSCs enhance the therapeutic efficacy of reperfusion therapy following stroke in rats. METHODS: First, to establish a transient middle cerebral artery occlusion (MCAO) model displaying approximately identical neurologic function and lesion volume as seen in permanent MCAO (pMCAO) at day 7 after stroke induction, we transiently occluded the MCA for 90, 110, and 120 minutes. We found that the 110-minute occlusion met these criteria and was used as the transient MCAO (tMCAO) model. Next, 4 MCAO groups were used to compare the therapeutic efficacy of infused MSCs: (1) pMCAO+vehicle, (2) tMCAO+vehicle, (3) pMCAO+MSC, and (4) tMCAO+MSC. Our ischemic model was a unique ischemic model system in which both pMCAO and tMCAO provided similar outcomes during the study period in the groups without MSC infusion groups. Behavioral performance, ischemic volume, and regional cerebral blood flow (rCBF) using arterial spin labeling-magnetic resonance imaging and histologic evaluation of microvasculature was performed. RESULTS: The behavioral function, rCBF, and restoration of microvasculature were greater in group 4 than in group 3. Thus, infused MSCs facilitated the therapeutic efficacy of MCA reperfusion in this rat model system. CONCLUSIONS: Intravenous infusion of MSCs may enhance therapeutic efficacy of reperfusion therapy.

    DOI： 10.1016/j.wneu.2021.02.056

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  • Intravenous infusion of mesenchymal stem cells delays disease progression in the SOD1G93A transgenic amyotrophic lateral sclerosis rat model. International journal

    Hirotoshi Magota, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Ryo Ukai, Ryo Kiyose, Rie Onodera, Jeffery D Kocsis, Osamu Honmou

    Brain research   1757   147296 - 147296   2021.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    ALS is a devastating neurodegenerative disease with few curative strategies. Both sporadic and familial ALS display common clinical features that show progressive paralysis. The pathogenesis remains unclear, but disruption of the blood-spinal cord barrier (BSCB) may contribute to the degeneration of motor neurons. Thus, restoration of the disrupted BSCB and neuroprotection for degenerating motor neurons could be therapeutic targets. We tested the hypothesis that an intravenous infusion of MSCs would delay disease progression through the preservation of BSCB function and increased expression of a neurotrophic factor, neurturin, in SOD1G93A ALS rats. When the open-field locomotor function was under 16 on the Basso, Beattie, and Bresnahan (BBB) scoring scale, the rats were randomized into two groups; one received an intravenous infusion of MSCs, while the other received vehicle alone. Locomotor function was recorded using BBB scoring and rotarod testing. Histological analyses, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), were performed. The MSC group exhibited reduced deterioration of locomotor activity compared to the vehicle group, which displayed progressive deterioration of hind limb function. We observed the protection of motor neuron loss and preservation of microvasculature using Evans blue leakage and immunohistochemical analyses in the MSC group. Confocal microscopy revealed infused green fluorescent protein+ (GFP+) MSCs in the spinal cord, and the GFP gene was detected by nested PCR. Neurturin expression levels were significantly higher in the MSC group. Thus, restoration of the BSCB and the protection of motor neurons might be contributing mechanisms to delay disease progression in SOD1G93A ALS rats.

    DOI： 10.1016/j.brainres.2021.147296

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  • Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series. International journal

    Osamu Honmou, Toshihiko Yamashita, Tomonori Morita, Tsutomu Oshigiri, Ryosuke Hirota, Satoshi Iyama, Junji Kato, Yuichi Sasaki, Sumio Ishiai, Yoichi M Ito, Ai Namioka, Takahiro Namioka, Masahito Nakazaki, Yuko Kataoka-Sasaki, Rie Onodera, Shinichi Oka, Masanori Sasaki, Stephen G Waxman, Jeffery D Kocsis

    Clinical neurology and neurosurgery   203   106565 - 106565   2021.4

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    BACKGROUND: Although spinal cord injury (SCI) is a major cause of disability, current therapeutic options remain limited. Recent progress in cellular therapy with mesenchymal stem cells (MSCs) has provided improved function in animal models of SCI. We investigated the safety and feasibility of intravenous infusion of MSCs for SCI patients and assessed functional status after MSC infusion. METHODS: In this phase 2 study of intravenous infusion of autologous MSCs cultured in auto-serum, a single infusion of MSCs under Good Manufacturing Practice (GMP) production was delivered in 13 SCI patients. In addition to assessing feasibility and safety, neurological function was assessed using the American Spinal Injury Association Impairment Scale (ASIA), International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92). Ability of daily living was assessed using Spinal Cord Independence Measure (SCIM-III). The study protocol was based on advice provided by the Pharmaceuticals and Medical Devices Agency in Japan. The trial was registered with the Japan Medical Association (JMA-IIA00154). RESULTS: No serious adverse events were associated with MSC injection. There was neurologic improvement based on ASIA grade in 12 of the 13 patients at six months post-MSC infusion. Five of six patients classified as ASIA A prior to MSC infusion improved to ASIA B (3/6) or ASIA C (2/6), two ASIA B patients improved to ASIA C (1/2) or ASIA D (1/2), five ASIA C patients improved and reached a functional status of ASIA D (5/5). Notably, improvement from ASIA C to ASIA D was observed one day following MSC infusion for all five patients. Assessment of both ISCSCI-92, SCIM-III also demonstrated functional improvements at six months after MSC infusion, compared to the scores prior to MSC infusion in all patients. CONCLUSION: While we emphasize that this study was unblinded, and does not exclude placebo effects or a contribution of endogenous recovery or observer bias, our observations provide evidence supporting the feasibility, safety and functional improvements of infused MSCs into patients with SCI.

    DOI： 10.1016/j.clineuro.2021.106565

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  • Prolonged lifespan in a spontaneously hypertensive rat (stroke prone) model following intravenous infusion of mesenchymal stem cells. International journal

    Masahito Nakazaki, Shinichi Oka, Masanori Sasaki, Yuko Kataoka-Sasaki, Hiroshi Nagahama, Kazuo Hashi, Jeffery D Kocsis, Osamu Honmou

    Heliyon   6 ( 12 )   e05833   2020.12

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    Intravenous infusion of mesenchymal stem cells (MSCs) has been reported to provide therapeutic efficacy via microvascular remodeling in a spontaneously hypertensive rat. In this study, we demonstrate that intravenous infusion of MSCs increased the survival rate in a spontaneously hypertensive (stroke prone) rat model in which organs including kidney, brain, heart and liver are damaged during aging due to spontaneous hypertension. Gene expression analysis indicated that infused MSCs activates transforming growth factor-β1-smad3/forkhead box O1 signaling pathway. Renal dysfunction was recovered after MSC infusion. Collectively, intravenous infusion of MSC may extend lifespan in this model system.

    DOI： 10.1016/j.heliyon.2020.e05833

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  • Intravenous delivery of mesenchymal stem cells protects both white and gray matter in spinal cord ischemia. International journal

    Naomi Yasuda, Masanori Sasaki, Yuko Kataoka-Sasaki, Hiroshi Nagahama, Jeffery D Kocsis, Nobuyoshi Kawaharada, Osamu Honmou

    Brain research   1747   147040 - 147040   2020.11

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    Ischemic spinal cord injury (iSCI) is a devastating complication of aortic surgery, with few strategies for prevention. Intravenous infusion of mesenchymal stem cells (MSCs) for iSCI has been shown to provide functional improvement through protection of gray matter. The purpose of this study was to investigate additional mechanisms which may exert therapeutic efficacy in iSCI. Severe iSCI was created to occlude the descending aorta, which was cross-clamped 5 mm distal to the left subclavian artery for 16 min. One day after iSCI induction, iSCI rats were randomized into two groups: one received intravenous infusion of MSCs (MSC-group), the other received vehicle (no cells; vehicle-group). Locomotor function and in vivo MRI were recorded. H&E, Nissl and toluidine blue stainings, immunohistochemical analysis, diffusion tensor imaging (DTI), and the assessment of blood-spinal cord barrier (BSCB) stability were performed. MSC treated animals exhibited gradual improvement in hind-limb locomotor function during the 4-week study period; however the vehicle-treated group displayed persistent motor deficits. In the MSC-treated group we observed the protection of white and gray matter volume reduction of axonal and neuronal loss or degeneration and preservation of microvasculature including BSCB function. Intravenous infusion of MSCs may provide therapeutic efficacy to improve functional outcomes in a rat model of severe iSCI via protection of white and gray matter.

    DOI： 10.1016/j.brainres.2020.147040

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  • 脳梗塞と脊髄損傷等に対する骨髄間葉系幹細胞の静脈内投与による細胞移植療法

    佐々木 祐典, 本望 修

    神経治療学   37 ( 3 )   314 - 314   2020

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    Language：Japanese   Publisher：日本神経治療学会  

    DOI： 10.15082/jsnt.37.3_314

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  • Prevention of neointimal hyperplasia induced by an endovascular stent via intravenous infusion of mesenchymal stem cells. Reviewed

    Nakazaki M, Oka S, Sasaki M, Kataoka-Sasaki Y, Onodera R, Komatsu K, Iihoshi S, Hiroura M, Kawaguchi A, Kocsis JD, Honmou O

    Journal of neurosurgery   2019.10

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.3171/2019.7.jns19575

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  • Infusion of Mesenchymal Stem Cells and Rehabilitation Medicine for Spinal Cord Injury Patients

    Morita Tomonori, Sasaki Masanori, Honmou Osamu, Yamashita Toshihiko

    The Japanese Journal of Rehabilitation Medicine   56 ( 7 )   552 - 554   2019.7

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    Language：Japanese   Publisher：The Japanese Association of Rehabilitation Medicine  

    Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I029914954

    DOI： 10.2490/jjrmc.56.552

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  • Intravenous infusion of mesenchymal stem cells improves impaired cognitive function in a cerebral small vessel disease model. Reviewed

    Nakazaki M, Sasaki M, Kataoka-Sasaki Y, Oka S, Suzuki J, Sasaki Y, Nagahama H, Hashi K, Kocsis JD, Honmou O

    Neuroscience   408   361 - 377   2019.6

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  • 骨髄間葉系幹細胞の静脈内投与による脊髄損傷治療

    47 ( 5 )   421 - 425   2019.5

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  • 脳梗塞と脊髄損傷等に対する骨髄間葉系幹細胞の静脈内投与による細胞移植療法

    佐々木 祐典, 本望 修

    神経治療学   36 ( 6 )   S108 - S108   2019

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    Language：Japanese   Publisher：日本神経治療学会  

    DOI： 10.15082/jsnt.36.6_s108

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  • Intravenous infusion of mesenchymal stem cells for protection against brainstem infarction in a persistent basilar artery occlusion model in the adult rat. Reviewed

    Namioka A, Namioka T, Sasaki M, Kataoka-Sasaki Y, Oka S, Nakazaki M, Onodera R, Suzuki J, Sasaki Y, Nagahama H, Kocsis JD, Honmou O

    Journal of neurosurgery   1 - 9   2018.10

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  • Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction. Reviewed

    Namioka T, Namioka A, Sasaki M, Kataoka-Sasaki Y, Oka S, Nakazaki M, Onodera R, Suzuki J, Sasaki Y, Nagahama H, Kocsis JD, Honmou O

    Journal of neurosurgery   1 - 8   2018.10

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  • Actin, alpha, cardiac muscle 1 (ACTC1) knockdown inhibits the migration of glioblastoma cells in vitro. International journal

    Masahiko Wanibuchi, Shunya Ohtaki, Satoshi Ookawa, Yuko Kataoka-Sasaki, Masanori Sasaki, Shinichi Oka, Yusuke Kimura, Yukinori Akiyama, Takeshi Mikami, Nobuhiro Mikuni, Jeffery D Kocsis, Osamu Honmou

    Journal of the neurological sciences   392   117 - 121   2018.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Recurrence is inevitable in glioblastomas (GBMs) and requires multifactorial processes. One of the factors that cause recurrence is the strong migratory capacity of GBM cells. We recently reported that actin, alpha, cardiac muscle 1 (ACTC1) could serve as a marker to detect GBM migration in clinical cases. OBJECTIVE: This study aimed to clarify whether the knockdown of highly expressed ACTC1 can inhibit the migratory capacity of cells in the GBM cell line. METHODS: ACTC1 expression was examined using immunocytochemistry and droplet digital polymerase chain reaction. The motility of GBM cells that were either treated with siRNA to knock down ACTC1 or untreated were investigated using a time-lapse study in vitro. RESULTS: The relatively high ACTC1 expression was confirmed in a GBM cell line, i.e., U87MG. The ACTC1 expression in U87MG cells was significantly inhibited by ACTC1-siRNA (p < 0.05). A cell movement tracking assay using time-lapse imaging demonstrated the inhibition of U87MG cell migration by ACTC1 knockdown. The quantitative cell migration analysis demonstrated that the distance traversed during 72 h was 3607 ± 458 (median ± SD) μm by untreated U87MG cells and 3570 ± 748 μm by negative control siRNA-treated cells. However, the distance migrated by ACTC1-siRNA-treated cells during 72 h was significantly shorter (1265 ± 457 μm, p < 0.01) than the controls. CONCLUSION: ACTC1 knockdown inhibits U87MG cell migration.

    DOI： 10.1016/j.jns.2018.07.013

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  • Preservation of interhemispheric cortical connections through corpus callosum following intravenous infusion of mesenchymal stem cells in a rat model of cerebral infarction. Reviewed

    Nagahama H, Nakazaki M, Sasaki M, Kataoka-Sasaki Y, Namioka T, Namioka A, Oka S, Onodera R, Suzuki J, Sasaki Y, Kocsis JD, Honmou O

    Brain research   1695   37 - 44   2018.9

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  • 脊髄損傷患者に対する自家培養骨髄間葉系幹細胞(MSC)の静脈投与におけるDTI-MRIを用いた脊髄・脳plasticity解析

    岡 真一, 廣田 亮介, 押切 勉, 森田 智慶, 長濱 宏史, 中崎 公仁, 佐々木 優子, 佐々木 祐典, 本望 修, 山下 敏彦

    日本整形外科学会雑誌   92 ( 8 )   S1840 - S1840   2018.8

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    Language：Japanese   Publisher：(公社)日本整形外科学会  

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  • Intravenous Infusion of Mesenchymal Stem Cells Alters Motor Cortex Gene Expression in a Rat Model of Acute Spinal Cord Injury. Reviewed

    Oshigiri T, Sasaki T, Sasaki M, Kataoka-Sasaki Y, Nakazaki M, Oka S, Morita T, Hirota R, Yoshimoto M, Yamashita T, Hashimoto-Torii K, Honmou O

    Journal of neurotrauma   2018.8

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1089/neu.2018.5793

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  • Functional recovery after the systemic administration of mesenchymal stem cells in a rat model of neonatal hypoxia-ischemia. Reviewed

    Sakai T, Sasaki M, Kataoka-Sasaki Y, Oka S, Nakazaki M, Fukumura S, Kobayashi M, Tsutsumi H, Kocsis JD, Honmou O

    Journal of neurosurgery. Pediatrics   2018.8

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.3171/2018.5.peds1845

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  • 放射線技術学を用いた先端生命科学研究 前臨床MRIを用いた脳梗塞に対する再生治療メカニズムの評価

    長濱 宏史, 鈴木 淳平, 佐々木 祐典, 中崎 公仁, 本望 修

    日本放射線技術学会雑誌   74 ( 7 )   722 - 725   2018.7

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    Ichushi

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  • Accelerating Cell Therapy for Stroke in Japan: Regulatory Framework and Guidelines on Development of Cell-Based Products. Reviewed International journal

    Kiyohiro Houkin, Hideo Shichinohe, Koji Abe, Teruyo Arato, Mari Dezawa, Osamu Honmou, Nobutaka Horie, Yasuo Katayama, Kohsuke Kudo, Satoshi Kuroda, Tomohiro Matsuyama, Ichiro Miyai, Izumi Nagata, Kuniyasu Niizuma, Ken Sakushima, Masanori Sasaki, Norihiro Sato, Kenji Sawanobori, Satoshi Suda, Akihiko Taguchi, Teiji Tominaga, Haruko Yamamoto, Toru Yamashita, Toshiki Yoshimine

    Stroke   49 ( 4 )   e145-e152   2018.4

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    DOI： 10.1161/STROKEAHA.117.019216

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  • Intravenous Infusion of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Erectile Dysfunction Following Cavernous Nerve Injury in Rats. Reviewed

    Matsuda Y, Sasaki M, Kataoka-Sasaki Y, Takayanagi A, Kobayashi K, Oka S, Nakazaki M, Masumori N, Kocsis JD, Honmou O

    Sexual medicine   2018.3

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    DOI： 10.1016/j.esxm.2017.10.005

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  • Intravenous infusion of mesenchymal stem cells reduces epileptogenesis in a rat model of status epilepticus. Reviewed

    Fukumura S, Sasaki M, Kataoka-Sasaki Y, Oka S, Nakazaki M, Nagahama H, Morita T, Sakai T, Tsutsumi H, Kocsis JD, Honmou O

    Epilepsy research   141   56 - 63   2018.3

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  • Digital Polymerase Chain Reaction Quantification of SERPINA1 Predicts Prognosis in High-Grade Glioma. International journal

    Satoshi Ookawa, Masahiko Wanibuchi, Yuko Kataoka-Sasaki, Masanori Sasaki, Shinichi Oka, Shunya Ohtaki, Shouhei Noshiro, Katsuya Komatsu, Yukinori Akiyama, Takeshi Mikami, Nobuhiro Mikuni, Jeffery D Kocsis, Osamu Honmou

    World neurosurgery   111   e783-e789   2018.3

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    BACKGROUND: SERPINA1 plays an anti-inflammatory role in protecting tissues from proteolytic mechanisms. SERPINA1 is positive in gliomas by immunohistochemical analysis; however, the role of SERPINA1, including the relationship with prognosis, has been uncertain. In recent years, digital polymerase chain reaction (PCR) has provided ultra-sensitive assessment of messenger RNA expression from formalin-fixed paraffin-embedded (FFPE) tissues. OBJECTIVE: In this study, we quantitatively determined the expression of SERPINA1 in high-grade gliomas (HGGs) using digital PCR, and we analyzed its relationship with prognosis. METHODS: Twenty-nine FFPE surgical samples from patients with HGGs (7 of World Health Organization [WHO] grade III and 22 of WHO grade IV), and human glioblastoma cell lines, U87 and U118, were used for analysis. A qualitative assessment using immunostaining and quantitative assessment using digital PCR were performed to assess the expression of SERPINA1. RESULTS: The expression of SERPINA1 was demonstrated in glioma tissues and glioblastoma multiforme cell lines by immunostaining. Digital PCR analysis showed that SERPINA1 was expressed in 14.3% and 63.6% of the tissues from patients with grade III and grade IV HGG, respectively (P = 0.035). The median overall survival of 38.8 months in the low SERPINA1 expression group was longer than that of 15.3 months in the high expression group (P = 0.030). CONCLUSIONS: The frequency and the amount of SERPINA1 expression were higher in grade IV than in grade III HGGs. The high expression of SERPINA1 indicates a poor prognosis of HGGs.

    DOI： 10.1016/j.wneu.2017.12.166

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  • [8. Evaluation of the Therapeutic Mechanisms in Regeneration Therapy for Cerebral Infarction Using Pre-clinical Magnetic Resonance Imaging]. Reviewed

    Nagahama H, Suzuki J, Sasaki M, Nakazaki M, Honmou O

    Nihon Hoshasen Gijutsu Gakkai zasshi   74 ( 7 )   722 - 725   2018

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  • Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats Reviewed

    Masahito Nakazaki, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Takahiro Namioka, Ai Namioka, Rie Onodera, Junpei Suzuki, Yuichi Sasaki, Hiroshi Nagahama, Takeshi Mikami, Masahiko Wanibuchi, Jeffery D. Kocsis, Osamu Honmou

    JOURNAL OF NEUROSURGERY   127 ( 4 )   917 - 926   2017.10

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    DOI： 10.3171/2016.8.JNS16240

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  • Biological relevance of tissue factor and IL-6 in arteriovenous malformations. International journal

    Shouhei Noshiro, Takeshi Mikami, Yuko Kataoka-Sasaki, Masanori Sasaki, Kazuo Hashi, Shunya Ohtaki, Masahiko Wanibuchi, Nobuhiro Mikuni, Jeffery D Kocsis, Osamu Honmou

    Neurosurgical review   40 ( 3 )   359 - 367   2017.7

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    Arteriovenous malformations (AVMs) are congenital abnormal vessels that shunt blood directly from the arterial to the venous system without a capillary bed. The underlying pathology of AVMs is not fully understood. The objective of the study was to determine the association between the expression patterns of tissue factor (TF) and interleukin-6 (IL-6) in AVMs with clinical and pathological findings. Eighteen cases of sporadic AVM with operative specimens were included in this study. The expression of messenger RNA (mRNA) of TF and IL-6 was assayed, and association with clinical factors was investigated. The distribution of TF and IL-6 was examined with immunofluorescence. The mRNA expression of TF was significantly higher in AVM specimens than in control tissues (P = 0.002) and significantly higher in the symptomatic group than in the asymptomatic group (P = 0.037). The mRNA expression of IL-6 was likewise significantly higher in AVM specimens than in control tissues (P = 0.038). Examination of immunostained sections indicated that TF+ cells were also positive for IL-6 and were distributed around normal endothelial cells and pericytes. Moreover, TF+/IL-6+ cells also expressed CD31, vascular endothelial growth factor receptor 2 (VEGFR2), and platelet-derived growth factor receptor beta (PDGFR-beta). These results suggest that TF is elevated in AVMs and that it mediates symptomatic events. IL-6 is associated with the angiogenic activity of TF, and both are present in the same abnormal endothelial cells and pericytes. These factors may have interactive effects and may serve in a prognostic role for AVMs.

    DOI： 10.1007/s10143-016-0780-1

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  • Co-expression of tissue factor and IL-6 in immature endothelial cells of cerebral cavernous malformations Reviewed

    Shouhei Noshiro, Takeshi Mikami, Yuko Kataoka-Sasaki, Masanori Sasaki, Hirofumi Ohnishi, Shunya Ohtaki, Masahiko Wanibuchi, Nobuhiro Mikuni, Jeffery D. Kocsis, Osamu Honmou

    JOURNAL OF CLINICAL NEUROSCIENCE   37   83 - 90   2017.3

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    DOI： 10.1016/j.jocn.2016.12.023

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  • ACTC1 as an invasion and prognosis marker in glioma Reviewed

    Shunya Ohtaki, Masahiko Wanibuchi, Yuko Kataoka-Sasaki, Masanori Sasaki, Shinichi Oka, Shouhei Noshiro, Yukinori Akiyama, Takeshi Mikami, Nobuhiro Mikuni, Jeffery D. Kocsis, Osamu Honmou

    JOURNAL OF NEUROSURGERY   126 ( 2 )   467 - 475   2017.2

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    DOI： 10.3171/2016.1.JNS152075

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  • Elevated brain derived neurotrophic factor (BDNF) levels in plasma but not serum reflect in vivo functional viability of infused mesenchymal stem cells after middle cerebral artery occlusion in rat. Reviewed

    Nakamura H, Sasaki Y, Sasaki M, Kataoka-Sasaki Y, Oka S, Nakazaki M, Namioka T, Namioka A, Onodera R, Suzuki J, Nagahama H, Mikami T, Wanibuchi M, Kocsis JD, Honmou O

    Journal of neurosurgical sciences   63 ( 1 )   42 - 49   2017.2

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  • Interleukin-13 receptor alpha 2 as a marker of poorer prognosis in high-grade astrocytomas. Reviewed

    Wanibuchi M, Kataoka-Sasaki Y, Sasaki M, Oka S, Otsuka Y, Yamaguchi M, Ohnishi H, Ohtaki S, Noshiro S, Ookawa S, Mikami T, Mikuni N, Honmou O

    Journal of neurosurgical sciences   2017.1

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  • Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats Reviewed

    Yuichi Sasaki, Masanori Sasaki, Yuko Kataoka-Sasaki, Masahito Nakazaki, Hiroshi Nagahama, Junpei Suzuki, Daiki Tateyama, Shinichi Oka, Takahiro Namioka, Ai Namioka, Rie Onodera, Takeshi Mikami, Masahiko Wanibuchi, Masafumi Kakizawa, Sumio Ishiai, Jeffery D. Kocsis, Osamu Honmou

    PHYSICAL THERAPY   96 ( 11 )   1791 - 1798   2016.11

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    DOI： 10.2522/ptj.20150504

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  • INTRAVENOUS INFUSION OF MESENCHYMAL STEM CELLS PROMOTES FUNCTIONAL RECOVERY IN A MODEL OF CHRONIC SPINAL CORD INJURY Reviewed

    Tomonori Morita, Masanori Sasaki, Yuko Kataoka-Sasaki, Masahito Nakazaki, Hiroshi Nagahama, Shinichi Oka, Tsutomu Oshigiri, Tsuneo Takebayashi, Toshihiko Yamashita, Jeffery D. Kocsis, Osamu Honmou

    NEUROSCIENCE   335   221 - 231   2016.10

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    DOI： 10.1016/j.neuroscience.2016.08.037

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  • Double balloon protection during carotid artery stenting for vulnerable carotid stenosis reduces the incidence of new brain lesions. Reviewed

    Nakazaki M, Nonaka T, Takahashi A, Yonemasu Y, Nomura T, Onda T, Honda O, Hashimoto Y, Ohnishi H, Sasaki M, Daibo M, Honmou O

    Acta neurochirurgica   158 ( 7 )   1377 - 1386   2016.7

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  • Cell Therapy for CNS Diseases

    Honmou Osamu

    Congress of the Japanese Physical Therapy Association   43   5 - 8   2016

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    DOI： 10.14900/cjpt.43S3.5

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  • Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury Reviewed

    Akio Takayanagi, Masanori Sasaki, Yuko Kataoka-Sasaki, Ko Kobayashi, Yohei Matsuda, Shinichi Oka, Naoya Masumori, Jeffery D. Kocsis, Osamu Honmou

    JOURNAL OF SEXUAL MEDICINE   12 ( 8 )   1713 - 1721   2015.8

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    DOI： 10.1111/jsm.12957

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  • [Treatment of cerebral ischemia using mesenchymal stem cell-clinical trial phase III]. Reviewed

    Nakazaki M, Oka S, Sasaki M, Honmou O

    118 ( 2 )   93 - 97   2015.2

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    Nakazaki M, Oka S, Sasaki M, Honmou O, Nihon Jibiinkoka Gakkai kaiho, 2015, vol. 118, no. 2, pp. 93-97

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  • Intravenous mesenchymal stem cell administration exhibits therapeutic effects against 6-hydroxydopamine-induced dopaminergic neurodegeneration and glial activation in rats. Reviewed

    Suzuki S, Kawamata J, Iwahara N, Matsumura A, Hisahara S, Matsushita T, Sasaki M, Honmou O, Shimohama S

    Neuroscience letters   584   276 - 281   2015.1

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  • 自家骨髄間葉系幹細胞の静脈投与による脊髄損傷治療 －医師主導治験Phase II－

    森田 智慶, 佐々木 祐典, 本望 修

    関節外科   34   85 - 90   2015

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    Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-25462227/

    CiNii Research

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  • ラット脳梗塞モデルに対する骨髄間葉系幹細胞移植後のfMRI による皮質賦活信号と運動機能改善との関連性 Reviewed

    Masahito Nakazaki, Junpei Suzuki, Masanori Sasaki, Shinichi Oka, Yuko Sasaki, Osamu Honmou

    Cerebral Blood Flow and Metabolism   25 ( 2 )   67 - 71   2014

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    DOI： 10.16977/cbfm.25.2_67

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  • Bilateral cortical hyperactivity detected by fMRI associates with improved motor function following intravenous infusion of mesenchymal stem cells in a rat stroke model Reviewed

    Junpei Suzuki, Masanori Sasaki, Kuniaki Harada, Michio Bando, Yuko Kataoka, Rie Onodera, Takeshi Mikami, Masahiko Wanibuchi, Nobuhiro Mikuni, Jeffery D. Kocsis, Osamu Honmou

    BRAIN RESEARCH   1497   15 - 22   2013.2

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    DOI： 10.1016/j.brainres.2012.12.028

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  • Therapeutic effects of human mesenchymal and hematopoietic stem cells on rotenone-treated parkinsonian mice. International journal

    Masatoshi Inden, Kazuyuki Takata, Kaneyasu Nishimura, Yoshihisa Kitamura, Eishi Ashihara, Kanji Yoshimoto, Hiroyoshi Ariga, Osamu Honmou, Shun Shimohama

    Journal of neuroscience research   91 ( 1 )   62 - 72   2013.1

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    To appreciate the potential applications of stem cell technology in neurodegenerative diseases, including Parkinson's disease (PD), it is important to understand the characteristics of the various types of stem cells. In this study, we designed a set of experiments to compare the ability of three types of human stem cells--mesenchymal stem cells (MSCs), bone marrow CD34(+) cells (BM), and cord blood CD34(+) cells (CB)--using rotenone-treated NOD/SCID mice. Rotenone was orally administered once daily at a dose of 30 mg/kg for 56 days to induce a parkinsonian phenotype. Intravenous delivery of CB into rotenone-treated mice was slightly more beneficial than that of MSCs or BM according to both histological and behavioral analyses. Human nucleus (hNu)(+) cells, which are a specific marker of human cells, were observed in the striatum of rotenone-treated mice transplanted with stem cells. These hNu(+) cells expressed tyrosine hydroxylase (TH). Additionally, α-synuclein(+)/TH(+) cells in the substantia nigra pars compacta decreased significantly following stem cell transplantation. Immunohistochemical analysis also revealed that chronic exposure to rotenone decreased glial cell line-derived neurotrophic factor immunoreactivity and that the reduction was improved by each stem cell transplantation. Gene expression analyses revealed that MSCs, BM, and CB expressed several neurotrophic factors. These results suggest that the beneficial effects of intravenous delivery of stem cells into rotenone-treated mice may result not only from a neurotrophic effect but also from endogenous brain repair mechanisms and the potential of intravenous delivery of stem cells derived from an autologous source for clinical applications in PD.

    DOI： 10.1002/jnr.23128

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  • Expression of aquaporin-4 augments cytotoxic brain edema after traumatic brain injury during acute ethanol exposure Reviewed

    Katada R, Nishitani Y, Honmou O, Mizuo K, Okazaki S, Tateda K, Watanabe S, Matsumoto H

    Am. J. Pathol   180   17 - 23   2012

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    DOI： 10.1016/j.ajpath.2011.09.011

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  • Bone marrow stem cells in experimental stroke Reviewed

    Jeffery D. Kocsis, Osamu Honmou

    FUNCTIONAL NEURAL TRANSPLANTATION III PRIMARY AND STEM CELL THERAPIES FOR BRAIN REPAIR, PT II   201   79 - 98   2012

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    DOI： 10.1016/B978-0-444-59544-7.00005-6

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  • Development of a Middle Cerebral Artery Occlusion Model in the Nonhuman Primate and a Safety Study of IV Infusion of Human Mesenchymal Stem Cells Reviewed

    Masanori Sasaki, Osamu Honmou, Christine Radtke, Jeffery D. Kocsis

    PLOS ONE   6 ( 10 )   2011.10

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    DOI： 10.1371/journal.pone.0026577

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  • Mesenchymal stem cells transmigrate across brain microvascular endothelial cell monolayers through transiently formed inter-endothelial gaps. Reviewed

    Matsushita T, Kibayashi T, Katayama T, Yamashita Y, Suzuki S, Kawamata J, Honmou O, Minami M, Shimohama S

    Neuroscience letters   502   41 - 45   2011.9

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  • Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Reviewed

    Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, Waxman SG, Kocsis JD

    Brain : a journal of neurology   134   1790 - 1807   2011.6

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  • Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Reviewed

    Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K, Hamada H, Kocsis JD

    Brain research   1343   226 - 235   2010.7

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  • Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia. Reviewed

    Komatsu K, Honmou O, Suzuki J, Houkin K, Hamada H, Kocsis JD

    Brain research   1334   84 - 92   2010.6

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  • Stem cell therapy for cerebral ischemia Reviewed

    Osamu Honmou, Kiyohiro Houkin

    Neurological Surgery   38 ( 6 )   515 - 520   2010.6

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  • Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia. Reviewed

    Zheng W, Honmou O, Miyata K, Harada K, Suzuki J, Liu H, Houkin K, Hamada H, Kocsis JD

    Brain research   1310   8 - 16   2010.1

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  • 脳梗塞に対する骨髄幹細胞療法

    本望 修, 大石 美里, 宝金 清博

    東北脳血管障害研究会学術集会記録集   31回   73 - 78   2009.12

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  • Prior ethanol injection promotes brain edema after traumatic brain injury. Reviewed

    Katada R, Nishitani Y, Honmou O, Okazaki S, Houkin K, Matsumoto H

    Journal of neurotrauma   26   2015 - 2025   2009.11

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  • BDNF-hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. Reviewed

    Sasaki M, Radtke C, Tan AM, Zhao P, Hamada H, Houkin K, Honmou O, Kocsis JD

    The Journal of neuroscience : the official journal of the Society for Neuroscience   29   14932 - 14941   2009.11

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  • 【ここまできた再生医学・再生医療】最先端の再生医療 骨髄幹細胞移植による脳梗塞治療

    本望 修, 宝金 清博

    Surgery Frontier   16 ( 3 )   315,265 - 266   2009.9

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  • 【神経再生臨床応用】骨髄幹細胞を用いた脳梗塞の臨床試験

    本望 修, 大石 美里, 宝金 清博

    脳21   12 ( 3 )   318 - 321   2009.7

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  • Effect of Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells on Mice Infected with Prions Reviewed

    Chang-Hyun Song, Osamu Honmou, Natsuo Ohsawa, Kiminori Nakamura, Hirofumi Hamada, Hidefumi Furuoka, Rie Hasebe, Motohiro Horiuchi

    JOURNAL OF VIROLOGY   83 ( 11 )   5918 - 5927   2009.6

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    DOI： 10.1128/JVI.00165-09

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  • Traumatic injury of spinal axons Reviewed

    Osamu Honmou, Wise Young

    The Axon: Structure, Function and Pathophysiology   2009.5

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    DOI： 10.1093/acprof:oso/9780195082937.003.0025

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  • 脳卒中 脳血管障害の再生医療

    本望 修, 宝金 清博

    神経治療学   26 ( 3 )   294 - 294   2009.5

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  • Spinal cord infarct as the initial clinical presentation of intravascular malignant lymphomatosis Reviewed International journal

    He Liu, Izumi Koyanagi, Hideki Chiba, Masahiro Wanibuchi, Osamu Honmou, Toshiaki Yamaki, Kiyohiro Houkin

    JOURNAL OF CLINICAL NEUROSCIENCE   16 ( 4 )   570 - 573   2009.4

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    DOI： 10.1016/j.jocn.2008.04.027

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  • Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia. Reviewed

    Toyama K, Honmou O, Harada K, Suzuki J, Houkin K, Hamada H, Kocsis JD

    Experimental neurology   216   47 - 55   2009.3

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  • 心肺停止後全脳虚血に対する骨髄幹細胞移植の検討

    鄭 偉, 本望 修, 劉 赫, 原田 邦明, 鈴木 淳平, 宝金 清博

    脳循環代謝   20 ( 1 )   99 - 99   2008.11

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  • 脳虚血における脳保護・再生 どこまでできるか 脳梗塞における臨床応用

    本望 修, 宝金 清博

    脳循環代謝   20 ( 1 )   75 - 75   2008.11

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  • Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats. Reviewed

    Omori Y, Honmou O, Harada K, Suzuki J, Houkin K, Kocsis JD

    Brain research   1236   30 - 38   2008.10

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  • 自己骨髄間葉系幹細胞の静脈内投与による脳梗塞治療へ向けて

    本望 修, 宝金 清博, 松永 卓也

    日本脳神経外科学会総会CD-ROM抄録集   67回   2F - 06   2008.10

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  • 【脳梗塞治療の現状と展望】脳梗塞急性期の治療 再生医療(骨髄移植を中心に)

    本望 修, 宝金 清博

    神経治療学   25 ( 5 )   545 - 548   2008.9

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  • Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia Reviewed International journal

    Toshiyuki Onda, Osamu Honmou, Kuniaki Harada, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM   28 ( 2 )   329 - 340   2008.2

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    DOI： 10.1038/sj.jcbfm.9600527

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  • 脳梗塞に対する骨髄幹細胞治療

    本望 修, 宝金 清博

    日本医事新報   ( 4367 )   140 - 141   2008.1

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  • A mesodermal stem cell therapy for stroke Reviewed

    Osamu Honmou, Osamu Honmou

    Drug Delivery System   23 ( 5 )   526 - 528   2008

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    DOI： 10.2745/dds.23.526

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  • 【脳梗塞 病期と病態に基づいた治療戦略】脳梗塞の最前線 骨髄幹細胞を用いた再生医療

    本望 修, 宝金 清博

    カレントテラピー   25 ( 12 )   1023 - 1025   2007.12

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    Ichushi

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  • 心肺停止後全脳虚血に対する骨髄幹細胞移植の検討

    鄭 偉, 本望 修, 劉 赫, 原田 邦明, 鈴木 淳平, 宝金 清博

    日本脳神経外科学会総会CD-ROM抄録集   66回   2K - 11   2007.10

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  • 脳梗塞に対する自己骨髄幹細胞治療へ向けて

    本望 修, 宝金 清博, 松永 卓也, 新津 洋司郎, 山村 明範

    脳循環代謝   19 ( 2 )   113 - 113   2007.10

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  • 脳梗塞に対する骨髄幹細胞治療

    本望 修, 宝金 清博

    日本脳神経外科学会総会CD-ROM抄録集   66回   3I - 7   2007.10

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  • Mesenchymal stem cells derived from peripheral blood protects against ischemia Reviewed International journal

    Ryo Ukai, Osamu Honmou, Kuniaki Harada, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis

    JOURNAL OF NEUROTRAUMA   24 ( 3 )   508 - 520   2007.3

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    DOI： 10.1089/neu.2006.0161

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  • 脳梗塞に対するAngiopoietin-1産生ヒト骨髄幹細胞移植の検討

    恩田 敏之, 本望 修, 原田 邦明, 宝金 清博, 濱田 洋文

    脳卒中   29 ( 2 )   429 - 429   2007.3

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  • Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model. Reviewed

    Harada K, Honmou O, Liu H, Bando M, Houkin K, Kocsis JD

    Brain research   1134   206 - 213   2007.2

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  • Neural differentiation potential of peripheral blood- and bone-marrow-derived precursor cells. Reviewed

    Kim S, Honmou O, Kato K, Nonaka T, Houkin K, Hamada H, Kocsis JD

    Brain research   1123   27 - 33   2006.12

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  • Neurogenesisと神経再生医療 脳梗塞に対する骨髄幹細胞移植による脳循環の改善

    本望 修, 鵜飼 亮, 原田 邦明, 宝金 清博

    脳循環代謝   18 ( 4 )   189 - 191   2006.12

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  • Optimization of three-dimensional time-of-flight magnetic resonance angiography of the intracranial arteries Reviewed

    Kuniaki Harada, Osamu Honmou, Yoshihiro Odawara, Michio Bando, Kiyohiro Houkin

    NEUROLOGIA MEDICO-CHIRURGICA   46 ( 11 )   523 - 528   2006.11

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    DOI： 10.2176/nmc.46.523

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  • Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. Reviewed

    Horita Y, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD

    Journal of neuroscience research   84   1495 - 1504   2006.11

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  • [A cell therapy for stroke].

    Osamu Honmou, Kiyohiro Houkin

    Nihon rinsho. Japanese journal of clinical medicine   64 Suppl 7   664 - 6   2006.10

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  • Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat Reviewed

    T. Honma, O. Honmou, S. Iihoshi, K. Harada, K. Houkin, H. Hamada, J. D. Kocsis

    EXPERIMENTAL NEUROLOGY   199 ( 1 )   56 - 66   2006.5

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    DOI： 10.1016/j.expneurol.2005.05.004

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  • 骨髄幹細胞の移植による脳虚血モデル慢性期における機能回復

    金 相年, 本望 修, 宝金 清博

    脳卒中   28 ( 1 )   199 - 199   2006.3

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  • Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Reviewed

    Liu H, Honmou O, Harada K, Nakamura K, Houkin K, Hamada H, Kocsis JD

    Brain   129   2734 - 2745   2006

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  • PLGF遺伝子導入ヒト骨髄幹細胞の脳梗塞モデルへの移植

    劉 赫, 本望 修, 原田 明邦, 宝金 清博, 濱田 洋文

    脳卒中   27 ( 1 )   168 - 168   2005.4

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  • BDNF産生ヒト間葉系幹細胞の経静脈的移植による脳梗塞治療の検討

    野村 達史, 本望 修, 原田 邦明, 劉 赫, 寶金 清博, 中村 公則, 濱田 洋文

    脳卒中   27 ( 1 )   203 - 203   2005.4

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  • I.v. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat Reviewed

    T Nomura, O Honmou, K Harada, K Houkin, H Hamada, JD Kocsis

    NEUROSCIENCE   136 ( 1 )   161 - 169   2005

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    DOI： 10.1016/j.neuroscience.2005.06.062

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  • ラット脳梗塞モデルに対する経静脈的骨髄幹細胞移植療法

    本間 敏美, 本望 修, 原田 邦明, 備前 明子, 劉 赫, 野村 達史, 中村 公則, 濱田 洋文, 寶金 清博

    脳卒中   26 ( 1 )   185 - 185   2004.3

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  • 【再生医学】神経の再生戦略

    佐々木 祐典, 本望 修, 宝金 清博

    Surgery Frontier   10 ( 3 )   267 - 272   2003.9

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  • 間葉系幹細胞(MSC)を用いた浸潤性グリオーマ遺伝子治療の開発

    中村 公則, 伊藤 克礼, 河野 豊, 黒住 和彦, 佐々木 勝則, 備前 明子, 本望 修, 宝金 清博, 濱田 洋文

    日本癌学会総会記事   62回   325 - 325   2003.8

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  • 神経保護と神経再生 ラット脊髄脱髄疾患モデルに対する自家骨髄移植の投与方法および投与細胞数の比較

    井上 道夫, 本望 修, 岡 真一, 飯星 智史, 宝金 清博, 端 和夫

    日本神経外傷学会プログラム・抄録集   26回   129 - 129   2003.3

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  • 自家骨髄細胞の移植による脳梗塞治療の展望

    飯星 智史, 本望 修, 備前 明子, 井上 道夫, 本間 敏美, 宝金 清博, 端 和夫

    脳卒中   25 ( 1 )   168 - 168   2003.3

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  • 経静脈的自家骨髄細胞移植による脳梗塞の治療

    飯星 智史, 本望 修, 岡 真一, 井上 道夫, 宝金 清博, 端 和夫

    神経組織の成長・再生・移植研究会学術集会プログラム・予稿集   17回   36 - 36   2002.6

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  • 中枢性脱髄疾患モデルに対する経静脈的自家骨髄移植

    井上 道夫, 本望 修, 岡 真一, 飯星 智史, 宝金 清博, 端 和夫

    神経組織の成長・再生・移植研究会学術集会プログラム・予稿集   17回   38 - 38   2002.6

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  • 神経の再生と機能再建による新しいリハビリテーション医療 ヒト成人脳からの神経幹細胞の分離培養と脳卒中モデルでの機能回復

    本望 修, 岡 真一, 佐々木 祐典, 高橋 明, 田之岡 篤, 宝金 清博, 端 和夫

    脳卒中   24 ( 1 )   141 - 141   2002.4

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  • Functional repair of demyelinated spinal cord axons in the adult rat by transplantation of genetically-engineering Schwann cells Reviewed

    O Honmou, K Hashi, PA Felts, SG Waxman, JD Kocsis

    11TH INTERNATIONAL CONGRESS OF NEUROLOGICAL SURGERY, VOLS 1 AND 2   1909 - 1912   1997

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  • Pathogenesis of hyponatremia following subarachnoid hemorrhage due to ruptured cerebral aneurysm Reviewed

    Y Kurokawa, T Uede, M Ishiguro, O Honda, O Honmou, T Kato, M Wanibuchi

    SURGICAL NEUROLOGY   46 ( 5 )   500 - 507   1996.11

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  • Technical tactics to preserve cortical venous drainage in interhemispheric approach for anterior communicating artery aneurysms Reviewed

    Y. Kurokawa, T. Uede, O. Honda, T. Kato, M. Wanibuchi, O. Honmou, K. Hashi

    Neurological Surgery   22 ( 1 )   29 - 34   1994

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  • Ventriculoperitoneal shunt using a continuously variable-resistance valve for management of hydrocephalus, especially for cases mimicking simple brain atrophy

    Y. Kurokawa, T. Uede, O. Honmou, K. Ohta, O. Honda

    Neurological Surgery   20 ( 6 )   669 - 675   1992

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  • Significance of plasma atrial natriuretic peptide measurement during the management of hyponatremia in neurosurgical patients Reviewed

    Y. Kurokawa, T. Uede, O. Honda, T. Kato, O. Honmou

    Brain and Nerve   44 ( 4 )   359 - 364   1992

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  • A case presenting a severe paralytic ileus during the continuous intravenous injection of nicardipine hydrochloride Reviewed

    Y. Kurokawa, T. Uede, K. Ohta, O. Honmou

    Brain and Nerve   43 ( 1 )   77 - 80   1991

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MISC

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Awards

  • 北海道科学技術賞

    2020  

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  • 北海道新聞文化賞

    2019  

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  • 日本医師会医学研究奨励賞

    2013  

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  • 日本再生医療学会 感謝状

    2002  

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  • 日本分子脳神経外科研究会 感謝状

    2001  

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  • 日本分子脳神経外科研究会 感謝状

    2000  

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  • 日本脳神経外科コングレス 感謝状

    2000  

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  • 日本心臓財団研究奨励賞

    1999  

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Research Projects

  • Optimization of Mesenchymal Stem Cell Therapy for Spinal Cord Injury.

    Grant number：25K12366  2025.4 - 2028.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • Amplification Mechanisms of Neuroprotective and Neurotrophic Effects Mediated by Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles

    Grant number：25K12482  2025.4 - 2028.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • Mechanistic Analysis of Neural plasticity by Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells

    Grant number：25K12509  2025.4 - 2028.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • 脳梗塞に対するsmall Extracellular Vesicles静脈投与療法の治療メカニズムの解明

    Grant number：25K12323  2025.4 - 2028.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    鵜飼 亮, 佐々木 祐典, 横山 貴裕, 中崎 公仁, 本望 修

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • 神経障害性疼痛・脊髄障害性疼痛に対する間葉系幹細胞の治療メカニズムの解析

    Grant number：24K12313  2024.4 - 2027.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    福士 龍之介, 佐々木 祐典, 小原 尚, 廣田 亮介, 佐々木 優子, 山下 敏彦, 本望 修

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • 慢性期脳梗塞に対する骨髄幹細胞治療における至適リハビリ条件の探索

    Grant number：24K14250  2024.4 - 2027.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    山下 達郎, 佐々木 雄一, 佐々木 祐典, 鵜飼 亮, 岡 真一, 佐々木 優子, 本望 修, 中崎 公仁

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • 脳梗塞に対する骨髄幹細胞治療による神経回路の再構築の革新的MRIによる統合的解析

    Grant number：24K12246  2024.4 - 2027.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    長濱 宏史, 佐々木 祐典, 本望 修, 中崎 公仁

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • Therapeutic strategies for cerebral infarction and spinal cord injury by activating plasticity throughout the central nervous system

    Grant number：23K24447  2024.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Grant amount：\5460000 （ Direct Cost: \4200000 、 Indirect Cost：\1260000 ）

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  • 脳梗塞に対する複数回骨髄幹細胞投与における至適リハビリ条件の探索

    Grant number：23K10430  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    佐々木 雄一, 鵜飼 亮, 山下 達郎, 岡 真一, 佐々木 優子, 本望 修

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    近年、骨髄間葉系幹細胞（MSC）を用いた細胞療法(MSC治療)は、再生医療の分野で脳梗塞や脊髄損傷に対する新しい治療方法として注目されている。我々は、既にラット脳梗塞モデルに対するMSC治療にリハビリテーション（リハビリ）を併用すると、リハビリ単独群やMSC治療単独群よりも、さらに高い運動機能の回復が得られることを報告した。また、これまでの実験的脳梗塞に対するMSCの治療効果を示した研究では、MSCの単回投与がほとんどであったが、さらなる治療効果を得るために複数回投与に期待が集まっている。我々は、ラット慢性期脳梗塞モデルにMSCを複数回投与すると、単回投与群やvehicle群と比較して、脳梗塞体積に違いはないものの運動機能の改善が得られることを報告した。しかし、MSC複数回投与におけるリハビリテーション併用の効果を検討した研究はない。本研究では、MSC複数回投与に併用する適切な運動（リハビリ）の種類や頻度・強度を考慮し、回復経過を分子メカニズムなど様々な視点から詳細に比較解析することで、MSC複数回投与の治療効果を最大限に引き出すための新しいリハビリ方法を確立することを目的としている。特に、運動強度と運動時間をなどの負荷量に注目し、脳の可塑性のパターンの変化、神経回路の再構築、シナプス新生などの観点から解析を進めている。現在までに、本研究費によって、各運動負荷における実験的脳梗塞に対する治療効果の行動学的解析、MRI解析、神経トレーサーを用いた神経解剖学的解析などを行っている。以上のように、補助金は補助条件に従って、有効に使用されている。

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  • Bone marrow mesenchymal stem cell transplantation prevents concurrent progression of chronic kidney disease and associated cerebrovascular disease

    Grant number：23K08095  2023.4 - 2026.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • Intravenous infusion of exosome for the treatment of neonatal hypoxic ischemic encephalopathy

    Grant number：23K07338  2023.4 - 2026.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • 脊髄損傷に対する骨髄幹細胞による治療メカニズムに占めるミトコンドリア機能の解析

    Grant number：23K08547  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    佐々木 祐典, 鵜飼 亮, 岡 真一, 佐々木 優子, 本望 修

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    Grant amount：\4810000 （ Direct Cost: \3700000 、 Indirect Cost：\1110000 ）

    脊髄損傷後に神経症状の増悪をもたらす二次損傷の病態解明は重要である。近年、二次損傷に占めるミトコンドリアの役割に注目が集まっており、脊髄損傷後に生じるミトコンドリアの機能不全によるATP合成不全が惹起するエネルギー代謝不全、活性酸素の産生増加、神経毒性の増加などが神経症状の増悪に関与すると報告されている。一方、我々はこれまで、脊髄損傷ラットモデルおよび脊髄損傷患者に対する骨髄幹細胞の経静脈的投与 (MSC治療)による運動機能の改善を報告してきた。
    この中で、MSC治療後に、ミトコンドリアの代謝機能に関連する遺伝子群が存在することを見出した。本研究では、脊髄損傷に対しMSC治療を実施し、①損傷局所および②大脳皮質の神経系細胞内におけるミトコンドリアの機能の変化を詳細に解析することを計画した。これらの解析を通じて、MSC治療により惹起される神経機能の回復に貢献するメカニズムにミトコンドリアが強く関与していることを明らかにし、次世代の治療法の開発に展開することを最終的な目標として、これまでに雄性SDラット (250-300g)に実験的脊髄損傷 (IH-0400 Impactor)を作製後にMSCの経静脈的投与を行い (MSC群)、運動機能を評価した。さらに、細胞外フラックスアナライザー (Xfe96, Agilent)を用いて、ミトコンドリアエネルギー代謝機能である酸素消費速度 (oxygen consumption rate: OCR)および細胞外酸性化速度(extracellular acidification rate: ECAR)を測定の予備的実験を開始した。

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  • 脳梗塞と脊髄損傷に対する中枢神経系全域の可塑性賦活化による治療戦略の検討

    Grant number：22H03188  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    本望 修, 佐々木 祐典, 鵜飼 亮, 岡 真一, 佐々木 優子

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    Grant amount：\16900000 （ Direct Cost: \13000000 、 Indirect Cost：\3900000 ）

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  • Development of innovative treatments using next-generation exosomes for cerebral infarction

    Grant number：22K09239  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

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  • 脊損に対する骨髄幹細胞治療で介在ニューロンの関与で再構築された神経回路の解析

    Grant number：22K09361  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    小原 尚, 福士 龍之介, 廣田 亮介, 佐々木 祐典, 栗原 康太, 山下 敏彦, 佐々木 優子, 本望 修

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    Grant amount：\3770000 （ Direct Cost: \2900000 、 Indirect Cost：\870000 ）

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  • 健康寿命延長に関与する骨髄幹細胞の自己治癒能と全身の恒常性維持

    Grant number：22K11807  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    佐々木 優子, 佐々木 祐典, 鵜飼 亮, 岡 真一, 本望 修

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

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  • Development of novel treatments and elucidation of mechanisms for intractable epilepsy using bone marrow mesenchymal stem cells

    Grant number：22K07938  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

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  • 慢性期脳梗塞に対する骨髄幹細胞とリハビリ併用による脳のplasticityの解析

    Grant number：21K11194  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    山下 達郎, 佐々木 祐典, 本望 修, 鵜飼 亮

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    近年、骨髄間葉系幹細胞(MSC)を用いた細胞療法(MSC治療)は、再生医療の分野で脳梗塞や脊髄損傷に対する新しい治療方法として注目されている。MSC移植の治療メカニズムは、①サイトカインによる神経栄養作用、②血液脳関門機能の修復、③血管新生、④脱髄軸索の再有髄化、⑤神経再生による脳のplasticityの調節、と多段階・協奏的に作用することが判明しており、臨床上の神経症状の回復も、ほぼこれと平行して進むことが判明している。我々は、既にラット急性期脳梗塞モデルに対してMSC移植にリハビリを併用すると、リハビリ単独群やMSC移植単独群よりも、さらに高い運動機能の回復が得られるこという報告をした。MSCは、1)梗塞巣周囲に集積し、2)脳梗塞体積を減少させ、3)脳梗塞周辺領域のシナプス新生を誘導し、4)脳梁萎縮を抑制、するが、リハビリを併用すると、脳の可塑性のさらなる亢進を誘導することが可能となり、より高い治療効果が得られることを明らかにした。さらに慢性期脳梗塞モデルに対するMSC移植は、運動機能が改善されることを明らかにした。急性期と慢性期で病態は異なるが、MSCが発揮する多彩な治療メカニズムを考えると、慢性期にMSC移植とリハビリを併用することでさらなる治療効果が期待できると考えられる。本研究は、慢性期脳梗塞モデルに対するMSC移植にリハビリを併用することで、機能改善をもたらすメカニズムを脳の可塑性の変化に注目して解析することを目的としている。現在までに、本研究費によって、実験的慢性期脳梗塞に対する治療効果の行動学的解析、MRI解析、神経トレーサーを用いた神経解剖学的解析などを行っている。以上のように、補助金は補助条件に従って、有効に使用されている。

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  • Intravenous infusion of mesenchymal stem cells for chronic spinal cord ischemia

    Grant number：21K08871  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

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  • Reconstructed neural circuits following intravenous infusion of mesenchymal stem cells in a rat model of experimental cerebral ischemia

    Grant number：21K09104  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

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  • 骨髄幹細胞治療における機能活性モニタリングと機能予後バイオマーカーの開発

    Grant number：21K09131  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    中村 秀之, 佐々木 祐典, 佐々木 優子, 本望 修, 鵜飼 亮, 横山 貴裕

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    我々は、脳梗塞に対する骨髄間葉系幹細胞（Ｍｅｓｅｎｃｈｙｍａｌ ｓｔｅｍｃｅｌｌｓ：ＭＳＣ）の経静脈的投与(ＭＳＣ治療）による良好な治療効果を報告してきた。我々のこれまでの基礎研究において、ラット脳梗塞モデルを用いた実験を行い、ＭＳＣ治療後の血漿中ＢＤＮＦは、投与されたＭＳＣの機能的バイオマーカーとなりうる可能性があることを報告した (Nakamura et al., 2017) 本研究では、血漿中ＢＤＮＦの推移が、機能活性の指標に留まらず、脳梗塞の機能予後と相関するのかどうかを検証することを計画しており、さらに、機能活性や機能予後を示す新しいバイオマーカーを探索することを目的としている。これまでに、①医師主導治験患者の血漿中ＢＤＮＦ測定、および、②ラットＭＣＡＯモデルにＭＳＣを投与し、血漿中ＢＤＮＦと機能予後の相関を検討することで、ＭＳＣ治療における機能活性モニタリングによる機能予後バイオマーカーの開発を行っている。①では、札幌医科大学附属病院に入院した患者から、経時的に採血を行い、血漿を分離し、ELISA法にてＢＤＮＦを測定し、ELIZA法によるＢＤＮＦの測定は、ＢＤＮＦ E-max immunoassay system (Promega) を用いる。②では、ラット脳梗塞モデルとして、中大脳動脈永久閉塞（MCAO）モデルを用いる。MCAOモデルは、Intraluminal thread methodを用いて作製し、脳梗塞発症6時間後にラットＭＳＣを経静脈的に投与し、末梢血を採取し、保存血から血漿を分離し、①同様にELISA法にてＢＤＮＦを測定する。観察期間中、並行して、トレッドミルによってラットの最大走行速度を測定し、運動機能および動物用MRIを用いて脳梗塞の体積を経時的に評価する。観察期間終了時に、血漿中ＢＤＮＦと運動機能から機能予後解析を継続して行うこととしている。以上のように、補助金は適切に使用し、予定通り進行中である。

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  • 脊髄損傷に対する骨髄間葉系幹細胞移植による、脳脊髄での可塑性亢進メカニズムの解析

    Grant number：21K09182  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    岡 真一, 佐々木 祐典, 横山 貴裕, 本望 修, 鵜飼 亮

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    令和3年度、当院にMSC治療を目的に入院した脊髄損傷症例は、おおよそ20例を数え、順調に症例数を積み重ねている状況である。全ての脊髄損傷症例の脳、脊髄のMRIデータを検証した。撮像時期は、原則、入院時、投与直前、 投与1ヶ月後、投与3ヶ月後、投与6ヶ月後の時点としていたかが、投与条件に当てはまらず投与を受けなかった症例や入院病床の調整の関係で、MRIの撮像を出来ない症例も散見された。特に脳DTIデータを用いたコネクトーム解析では、標準化の方法、使用する脳atlasの選択、ROI間の接続強度の閾値設定など、症例間でばらつきのない均一な解析を実施するためのパラメータの設定の検討を引き続き実施している。さらに、T1WI、T2WIなどを用いて大脳皮質厚や体積などの構造学的なデータ解析も同時に実施し、コネクトーム解析で得られた結果との比較も実施している。また、脊髄MRIでは、個々の症例においてDTI解析の可否や、定量的な解析を実施し、データの蓄積を行っている。撮像データの解析、特にDTIデータの解析を目的として高機能のパーソナルコンピューターを別途購入し、専用のアプリケーションにて解析を実施した。
    ラット脊髄損傷モデルに対して骨髄間葉系幹細胞(MSC)の経静脈投与することによって、中枢神経系にどのような神経回路の再構築(plasticity)が生じるかを検証するため、ラット胸髄Th9レベルの脊髄損傷モデルを作成し、動物用MRIでの撮像条件の最適化を検討した。8-9週齢のSDラットを購入し、ラット用脊髄損傷作 成装置(IH-0400 Impactor; PSI社製)を用いて、安定した損傷部位を作成できることを確認した。その後、動物実験用高磁場MRI装置にて、脳、脊髄おける各種プロトコール(T1、T2、DTI等)での撮像を行い、撮像条件の調整を行い最適な撮像条件の検討を行った。

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  • 脊髄障害性疼痛に対する骨髄間葉系幹細胞を用いた治療法の開発

    Grant number：21K09183  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    栗原 康太, 福士 龍之介, 廣田 亮介, 佐々木 祐典, 山下 敏彦, 押切 勉, 岡 真一, 佐々木 優子, 本望 修, 小原 尚

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    従来の脊髄損傷に対する研究は、運動機能の回復に焦点が置かれてきたが、近年は脊髄損傷に伴う二次的影響への関心が高まり、特に疼痛を含む異常感覚への治療介入によって、ADLやQOLが改善できると認識されつつある。しかし、その疼痛は難治性で、有効な治療法が確立されていないのが現状であり、新しい治療法の開発が期待されている。我々は、種々の中枢神経損傷モデルに対し、骨髄間葉系幹細胞(mesenchymal stem cells: MSC) の静脈内投与（MSC治療）が治療効果を有することを報告してきた。本研究の目的は、MSC治療が脊髄障害性疼痛に対し有効な治療法となり得るか検証することである。実験方法としては、ラット用脊髄損傷作製装置を用いて、SDラットのTh9レベルに実験的脊髄損傷を作製し、モデル作製後3日目にラットから採集・培養したMSCを経静脈的に投与し、観察期間終了後 まで飼育した。投与後の行動学的評価を経時的に行った。評価方法は、Basso Beattie Bresnahan (BBB)、後肢足底部中央にfilament を用いて機械刺激を与えるvon Frey filament test、後肢足底部中央に熱刺激を加え, 逃避反応時間を測定するRadiant heat testを用いた。本年の研究成果に関して、MSC投与後のBBB、von Frey filament test 、Radiant heat testによって、逃避反応閾値、時間を測定した結果、MSC投与群はVehicle投与群、Sham群と比較して、運動機能の改善が得られ、疼痛行動は抑制される可能性があることが判明した。

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  • Development of innovative treatment for spinal cord injury using next-generation exosomes

    Grant number：21K09231  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）

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  • 神経障害性疼痛に対する間葉系幹細胞の治療効果の検討

    Grant number：21K09282  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    福士 龍之介, 山下 敏彦, 本望 修, 佐々木 祐典, 佐々木 優子, 黄金 勲矢, 廣田 亮介, 押切 勉, 栗原 康太, 小原 尚

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    神経障害性疼痛は、神経障害の存在下に神経応答の過敏性が発現することにより生じる痛覚過敏、allodynia、自発痛のことを称し、整形外科で多い愁訴であるが、一般的な治療法では十分な除痛効果が得られない症例も存在する。我々は、末梢神経損傷モデルを含む種々の神経損傷モデルに対し、骨髄間葉系幹細胞 (mesenchymal stem cells: MSC) の静脈内投与（MSC治療）が治療効果を有することを報告してきた。本研究は、骨髄間葉系幹細胞 MSC治療により誘導される神経障害性疼痛の抑制効果の解析、MSC治療後の神経障害性疼痛に関する全神経系のダイナミックな変化の解析を目的にしている。実験方法としては、末梢神経障害モデルとして汎用されているSpared nerve injuryモデルを用いた。モデル作製後3日目にラットから採集・培養したMSCを経静脈的に投与し、観察期間終了後 (28日)まで飼育した。MSC投与群10匹、Vehicle投与群10匹、Sham群10匹を評価対象とし、投与後3、7、14、21、28日目に行動学的評価を行った。評価方法は後肢足底部中央にfilament を用いて機械刺激を与えるvon Frey filament test、後肢足底部中央に熱刺激を加え, 逃避反応時間を測定するRadiant heat testを用いた。覚醒下でvon Frey filamentによる触刺激と heat padによる熱刺激を後肢足底に加え、各刺激に対する逃避反応を観察し、allodyniaやhyperalgesiaの有無から、疼痛行動の抑制効果を評価した。本年の研究成果に関して、MSC投与後7、14、21、28日目のvon Frey filament test 、Radiant heat testによって、逃避反応閾値、時間を測定した結果、MSC投与群はVehicle投与群、Sham群と比較して、疼痛行動は抑制される可能性があることが判明した。

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  • 脊損に対する骨髄幹細胞治療後の網羅的遺伝子解析による“脳および脊髄の反応”の解明

    Grant number：20K09483  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    押切 勉, 廣田 亮介, 山下 敏彦, 岡 真一, 佐々木 優子, 本望 修, 栗原 康太, 福士 龍之介

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    我々は脊髄損傷患者に対する自己骨髄幹細胞(MSC)の静脈的投与を行った医師主導治験において、脳のMRI diffusion tensor imaging (DTI)を用いたコネクトーム解析を行い、脳のplasticityが亢進していることを見出した。さらに、最近では、脊髄損傷ラットモデルにMSC移植を行い、運動機能の回復が現れた移植3日目に大脳皮質運動野の網羅的遺伝子解析を行った結果、複数の遺伝子の発現量に変化があり、これらの遺伝子の多くは神経再生、plasticityの亢進に関与する遺伝子であることを報告した(Oshigiri et al.,2019)。そこで本申請では、先行研究を発展させ、大脳皮質の更なる解析に加えて脊髄損傷局所の網羅的遺伝子解析を複数の観察ポイントで行い、運動機能の改善に関与する遺伝子のプロファイルを解析し、中枢神経系全体の遺伝子発現の変化を総合的に考察することで、次世代の治療法に展開させることを目的とする。
    現在までに、本研究費によって、ラット脊髄圧座モデルを作成し、MSCを左大腿静脈より投与し、下肢運動機能の行動解析をBBBscore行い、投与群の優位性を認めた。移植後3日目および7日目の大脳皮質運動野のMicroarrayによる網羅的遺伝子解析を行っている。これまでのところ、移植後7日目と比較して、3日目の大脳皮質の遺伝子が大きく変化しており、運動機能回復に関連した遺伝子がいくつか判明され、その経時的な変化の解析を行っているところである。また、脊髄及び脳の組織から得られた複数タイムポイントの遺伝子情報を元に、複数のデータベース（Gene Ontology解析、パスウェイ解析、エンリッチ解析、タンパク質相互作用解析、プロモーター解析）を用いて、統合的に遺伝子発現解析を行う。
    以上のように、補助金は補助条件に従って、有効に使用されている。

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  • 脳梗塞に対する骨髄幹細胞治療における分子メカニズムに基づく至適リハビリ条件の探索

    Grant number：20K11212  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    佐々木 雄一, 佐々木 祐典, 岡 真一, 佐々木 優子, 本望 修, 山下 達郎, 鵜飼 亮

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    近年、骨髄間葉系幹細胞(MSC)を用いた細胞療法(MSC治療)は、再生医療の分野で脳梗塞や脊髄損傷に対する新しい治療方法として注目されている。我々は、既にラット脳梗塞モデルに対するMSC移植にリハビリを併用すると、リハビリ単独群やMSC移植単独群よりも、さらに高い運動機能の回復が得られるこという報告をし た。MSCは、1)梗塞巣周囲に集積し、2)脳梗塞体積を減少させ、3)脳梗塞周辺領域のシナプス新生を誘導し、4)脳梁萎縮を抑制、するが、リハビリを併用すると、脳の可塑性のさらなる亢進を誘導することが可能となり、より高い治療効果が得られることを明らかにした。しかし、実臨床に目を向けると、MSC治療とリハビリの至適なプロトコルの確立はなされておらず、様々な議論が絶えない状況である。一方、最近のリハビリの動向として、早期リハビリや高負荷・高頻度のリハビリの有用性、さらに、日常生活における適切な環境因子に注目が集まっている。本研究は、MSC移植に併用する適切な運動(リハビリ)の種類や頻度・強度 とともに、飼育環境も考慮し、回復経過を分子メカニズムなど様々な視点から詳細に比較解析することで、MSC移植の治療効果を最大限に引き出すための新しいリハビリ方法を確立することを目的としている。特に、運動強度と運動時間をなどの負荷量に注目し、脳の可塑性のパターンの変化、神経回路の再構築、シナプス新生などの観点から解析を進めている。現在までに、本研究費によって、各運動負荷における実験的脳梗塞に対する治療効果の行動学的解析、MRI解析、神経トレーサーを用いた神経解剖学的解析などを行っている。以上のように、補助金は補助条件に従って、有効に使用されている。

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  • 脊髄損傷に対する骨髄幹細胞治療でダイナミックに再構築された神経回路の機能解析

    Grant number：20H03793  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    佐々木 祐典, 廣田 亮介, 栗原 康太, 小原 尚, 横山 貴裕, 押切 勉, 岡 真一, 佐々木 優子, 寺島 嘉紀, 本望 修

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    Grant amount：\17290000 （ Direct Cost: \13300000 、 Indirect Cost：\3990000 ）

    我々は脊髄損傷動物モデルに対する骨髄間葉系幹細胞(mesenchymal stem cells: MSC)の経静脈的投与による機能回復のメカニズムとして、“損傷局所”における神経保護作用、血液脊髄関門の安定化、損傷軸索のsproutingや、損傷軸索の再生、再有髄化、シナプス新生等が多段階的に作用することにより、運動機能の回復に貢献することを明らかにしてきた。これらのメカニズムに加えて、損傷周囲および脳における神経回路のダイナミックな再構築によって、“中枢神経系全域の再生・plasticityの賦活化”が惹起される、という治療メカニズムも強く寄与している可能性があるのではないか、という仮説を検証することを目的としている。
    本研究では、実験的脊髄損傷に対するMSC治療後に惹起される損傷周囲および脳における神経回路の再構築を、順行性神経軸索トレーサーによる神経解剖学的トレーシング法、Ex vivo MRI Diffusion Tensor Tractography (DTT)などを駆使して、解明する予定である。特に、神経解剖学的解析においては、共焦点レーザー顕微鏡(Zeiss)、光シート顕微鏡（ミルテニーバイオテク）により画像を取得し、高精細3D/4D画像解析ソフトを用いた神経ファイバーのトレーシング、ヒートマップ解析等を行っている。これら一連の実験により、実験的脊髄損傷に対するMSC治療によってダイナミックに再構築された神経回路の解析を行うことが可能になると考えている。以上のように、補助金は適切に使用されている。

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  • Mesenchymal stem cells for brain injury of prematurity in a rat model.

    Grant number：20K08163  2020.4 - 2023.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

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  • 神経膠腫の浸潤機序解析と浸潤能を標的とした先駆的治療法の開発

    Grant number：20K09359  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    鰐渕 昌彦, 川端 信司, 佐々木 祐典, 平松 亮, 池田 直廉, 古瀬 元雅, 野々口 直助, 佐々木 優子, 本望 修

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    アクチンのisoformは６種類が知られている。それらのうち、肥大型心筋症との関連や心室中隔欠損症の責任遣伝子として注目されているのがACTC1（actin, alpha cardiac muscle 1）である。我々はACTC1が悪性脳腫瘍、特にグリオーマの予後や浸潤能に関与することを見出した。本研究ではACTC1の更なる役割を解明し、遺伝子ネットワークの解析や治療薬の開発に繋げることを目的としている。TCGA PanCancer Cell line Atlasに登録されている1,156種類のがん細胞株における遺伝子発現データを解析した結果、ACTC1は「上皮間葉転換」の主要なマーカー遣伝子であるFN1、SNAI1、ZEB1、TWIST1、VIM、FOXC2の発現量と相関があることを確認したので、ACTC1の発現と上皮間葉転換との関連について研究を行っている最中である。また、ACTC1のプロモータ配列に対し親和性の高い転写因子として、転写因子のデータベースより、SMARCA4、RB1、POLR2A、CBFA2T2、WT1、GLIS1が相関することを確認した。さらにヒトグリオーマ細胞株８株を用いてtranscriptome解析 を行った後、ACTC1の発現量と共変動を示す遺伝子を対象としてpathway解析を実施した.結果、Rap1、Hippo、Relaxin、Apelin、Sphingolipid、C-type lectin receptor及びOxytocinのsignaling pathwayがACTC1の発現に有意な関連を持つsignaling pathwayとして同定された。
    同様の手法を用いて、高悪性度髄膜腫や転移性脳腫瘍など、他の悪性脳腫瘍の細胞についてもACTC1の発現や役割の解析を行っている。

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  • The development of novel therapies for intractable epilepsy with bone marrow mesenchymal stem cells

    Grant number：19K08256  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Fukumura Shinobu

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    The present study tested the hypothesis that systemically infused mesenchymal stem cells (MSCs) improve epilepsy in a rat model of chronic epilepsy. Status epilepticus (SE) was induced using the lithium-pilocarpine injection. MSCs or vehicle (DMEM only, no cells) were administered intravenously to rats with chronic epilepsy on the 60th day after lithium-pilocarpine-induced SE. The number of seizures was lower in the MSC-treated group than in the vehicle-treated group. Furthermore, frequency analysis demonstrated that the percentage of gamma-band on the electroencephalography was also lower in the MSC-treated group than in the vehicle-treated group. These suggest that MSCs effectively reduced the number of seizures and excitability in the chronic phase of epilepsy.

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  • Extended lifespan induced by mesenchymal stem cells

    Grant number：19K11794  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Kataoka-Sasaki Yuko

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    In this study, we demonstrated that intravenous infusion of MSCs increased the survival rate in rat models of spontaneously hypertensive (stroke-prone) in which organs including kidney, brain, heart, and liver are damaged during aging due to spontaneous hypertension. Intravenous infusion of MSC may extend lifespan in addition to preventing the deterioration of motor and cognitive functions in the animal model.

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  • Mesenchymal stem cell therapy for experimental stroke

    Grant number：19K09461  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Honmou Osamu

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    In this study, we demonstrated that the therapeutic efficacy of intravenous infusion of mesenchymal stem cells (MSCs) was enhanced via induced neural plasticity in the whole brain using MRI diffusion tensor imaging. We also showed that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. Administration of MSCs is associated with the promotion of whole interhemispheric connectivity through the corpus callosum even in the chronic phase of cerebral infarction.

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  • Intravenous infusion of mesenchymal stem cells for spinal cord ischemia

    Grant number：18K08766  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Yasuda Naomi

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    Ischemic spinal cord injury (iSCI) is a devastating complication of aortic surgery, with few strategies for prevention. Intravenous infusion of mesenchymal stem cells (MSCs) for traumatic SCI has been shown. The purpose of this study was to investigate mechanisms which may exert therapeutic efficacy in iSCI.
    Severe iSCI was created to occlude the descending aorta. One day after iSCI induction, iSCI rats were randomized into two groups: one received intravenous infusion of MSCs, the other received vehicle.
    MSC treated animals exhibited gradual improvement of locomotor function during the 4-week study period; however the vehicle group displayed persistent motor deficits. In the MSC-treated group we observed the protection of white and gray matter volume reduction and preservation of microvasculature including BSCB function. Intravenous infusion of MSCs may provide therapeutic efficacy to improve functional outcomes in a rat model of severe iSCI via protection of white and gray matter.

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  • Analysis of accelerating plasticity in the brain following intravenous infusion of mesenchymal stem cells in spinal injury

    Grant number：18K08975  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OKA SHINICHI

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    Neurofunctional recovery in spinal cord injury following intravenous infusion of Mesenchymal stem cells has been reported. It is one of the most important mechanisms of functional improvement that remote responses occur in the brain as well as in the injured spinal cord. Therefore, we performed MRI analysis after MSC administration for spinal cord injury in patients and animal experimental models, and histological analysis for animal models at the same time, and clarified that neural circuit rearrangement occurred.

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  • Intravenous infusion of mesenchymal stem cells enhance plasticity in the brain of rat model of experimental spinal cord injury

    Grant number：18K09071  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Nagahama Hiroshi

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    The enhanced neural plasticity at the injured tissue and/or in the higher level of spinal cord and brain following intravenous infusion of MSCs in spinal cord injury (SCI) model was thought to be due to protection from neuronal, axonal loss or degeneration in the injured tissue, and stabilization of the blood-spinal cord barrier. Furthermore, we analyzed the variable genes expressed in the motor cortex at the 3 days post-MSC infusion, when functional improvement was observed, and found that there were changes in the expression levels of several genes, which may enhance neural plasticity. Consequently, we found that intravenous infusion of MSCs in SCI may promote the functional improvement through the enhanced neural plasticity induced at the injured tissue and at the upper spinal cord and brain.

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  • Analysis of the neural circuits reconstructed by interneurons in mesenchmal stem cell transplantation for spinal cord injury

    Grant number：18K09072  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Hirota Ryosuke

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    The reorganization of neural circuits in the brain after spinal cord injury has been previously reported using MRI diffusion tensor imaging and other techniques, but there are few reports using detailed neuroanatomical methods. The purpose of this study was to analyze in detail the reorganization of neural circuits in the brain after spinal cord injury using adeno-associated virus (AAV), which is known as a progressive neural tracer.
    AAV-8 carrying the CAG promoter was found to have high efficiency of transduction, adaptive tracking, and cell-selective labeling in the brain. Furthermore, analysis of the brain after spinal cord injury using the same vector suggested that neural circuit reconstruction had occurred.

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  • Intravenous infusion of mesenchymal stem cells alleviates interstitial cystitis/bladder pain syndrome in a Toll-like receptor-7 agonist-induced rat model

    Grant number：18K09199  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Tabata Hidetoshi

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    Loxoribine (LX), a TLR7 agonist, was instilled transurethrally into the bladders of female Sprague-Dawley rats. Then, intravenous infusion of MSCs or vehicle was conducted. Freezing behavior, voiding behaviors, and histological changes in the bladder were investigated. Quantitative real-time polymerase chain reaction was performed to analyze the mRNA expression levels of inflammatory cytokines. Green fluorescent protein (GFP)-positive MSCs were used for cell tracking. Freezing behavior was reduced in the MSC group, and voiding behaviors in the MSC group did not deteriorate. Hematoxylin-eosin staining showed that mucosal edema, leukocyte infiltration, and hemorrhage were suppressed in the MSC group. The relative expression of interferon-b-mRNA in the bladder of the MSC group was inhibited. Numerous GFP-positive MSCs were extensively distributed, mainly in the submucosal and mucosal layers of the inflammatory bladder wall.

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  • Intravenous infusion of mesenchymal stem cells for experimental ALS

    Grant number：18K08974  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Rie Onodera

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    We demonstrated that an intravenous infusion of MSCs delay disease progression through the preservation of BSCB function and increased expression of a neurotrophic factor, neurturin, in SOD1G93A ALS rats. The MSC group exhibited reduced deterioration of locomotor activity compared to the vehicle group, which displayed progressive deterioration of hind limb function. We observed the protection of motor neuron loss and preservation of microvasculature in the MSC group. Neurturin expression levels were significantly higher in the MSC group. Thus, restoration of the BSCB and the protection of motor neurons might be contributing mechanisms to delay disease progression in SOD1G93A ALS rats. We also showed that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion.

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  • Functional recovery following intravenous infusion of mesenchymal stem cells via induction of neural plasticity in chronic spinal cord injury

    Grant number：17K10902  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Morita Tomonori

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Intravenous infusion of mesenchymal stem cells (MSCs) has been shown to provide functional improvements in spinal cord injury (SCI) through local therapeutic mechanisms that provide neuroprotection, remyelination, and axonal sprouting. Recent evidence has demonstrated that remote responses in the brain, as well as local responses in the injured spinal cord, can be induced after SCI. In the present study, we examined the brain response that might be associated with the functional improvements induced by the infused MSCs after SCI. Genome-wide RNA profiling was performed in the motor cortex of SCI rats at 3 days post-MSC or vehicle infusion. Then, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) data revealed that the seven behaviorally-associated differentially expressed genes (DEGs) had significant correlations with the behavioral function. These behaviorally-associated DEGs may be related to the functional recovery after systemic infusion of MSCs in SCI.

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  • analysis of molecular mechanism of invasion in malignant gliomas and development of a novel treatment by inhibition of glioma cell migrations

    Grant number：17K10872  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Wanibuchi Masahiko

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Gliomas account for 24.1% of primary brain tumors. It is difficult to cure the disease with multimodality treatment combined with surgery, chemotherapy, and radiotherapy. The 5-year survival rate of glioblastoma which is the most malignant type of gliomas is only 10.1%. The reason for the poor prognosis is the invasive capacity, however, the factors and mechanisms of invasion or migration is still unknown.In this study, we found several factors which related to the prognosis of gliomas such as ACTC1 (actin alpha cardiac muscle 1), SERPINEA1, IL13 receptor alpha 2. Among these, ACTC1 was also closely related to the invasion of malignant gliomas. In addition, timelapse study of U87 malignant glioma cell line revealed gene knockdown of ACTC1 using by siRNA resulted in the inhibition of migration of glioma cells. The present study demonstrated that targeting of migration capacity of glioma cells may lead to the improvement of prognosis of malignant gliomas.

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  • Improvement in neural function following intravenous infusion of mesenchymal stem cells in experimental cerebral stroke

    Grant number：17K10901  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Suzuki Junpei

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    Intravenous of mesenchymal stem cells (MSCs) following cerebral infarction exerts functional recovery. Previous study has suggested potential therapeutic mechanisms that promote neuroprotection and synaptogenesis, secretion of neurotrophic factors, remodeling of neural circuits, and elevation of trophic factors. In addition to these mechanisms, we hypothesized that restored interhemispheric connectivity might be an additional mechanism of neural improvements. In this study, we have demonstrated that there was anatomical restoration of cortical interhemispheric connections after infused MSCs in middle cerebral artery occlusion (MCAO). These results suggest that distinct preservation of interhemispheric cortical connections through corpus callosum was preserved by intravenous infusion of MSCs. This anatomical preservation of the motor cortex in the contralateral hemisphere may contribute to improvements in neural function after MSC therapy for cerebral stroke.

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  • 筋萎縮性側索硬化症に対する骨髄間葉系幹細胞移植による新たな治療法の開発

    Grant number：17K10844  2017.4 - 2020.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    小野寺 理恵, 佐々木 祐典, 本望 修

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • Induced neural plasticity following combination of intravenous infusion of Mesenchymal Stem Cells and Rehabilitation after stroke in rats

    Grant number：17K01513  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Sasaki Yuichi

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    We investigated induced neural plasticity following combination of intravenous infusion of mesenchymal stem cells (MSCs) and rehabilitation after stroke in rats. The neural plasticity and plasma BDNF levels increased following MSC infusion. These results support the hypothesis that BDNF levels in plasma and DTI tractography might be appropriate to detect therapeutic efficacy in a rat model of ischemic stroke. Future research should be performed to establish a rehabilitation protocol that maximizes the therapeutic efficacy of combination of MSC therapy and rehabilitation.

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  • Analysis of neural functional recovery mechanism immediately after bone marrow stem cell transplantation for spinal cord injury

    Grant number：16K10830  2016.10 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Oshigiri Tsutomu

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    While functional recovery from transvenous administration of bone marrow mesenchymal stem cells (MSCs) to spinal cord injury (SCI) models has been reported, the role of the brain in spinal cord injury has attracted attention. In this study, MSCs were intravenously administered to acute-phase SCI rats, and 15 genes related to recovery of motor function were extracted from comprehensive gene expression analysis by brain microarray. This suggests that intravenous administration of MSC has neuroprotective and regenerating effects on the brain and is involved in recovery of motor function.

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  • The development of novel therapies for intractable epilepsy with bone marrow mesenchymal stem cells

    Grant number：16K09993  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Fukumura Shinobu

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    The present study tested the hypothesis that systemically infused mesenchymal stem cells (MSCs) reduce epileptogenesis by inhibiting neuronal cell death and suppressing aberrant MFS, leading to preservation of cognitive function in a rat model of epilepsy. Status epilepticus (SE) was induced using the lithium-pilocarpine injection. MSC infusion inhibited epileptogenesis and preserved cognitive function after SE. The infused MSCs preserved GAD67+ and NeuN+ hippocampal neurons. Furthermore, the MSC infusion suppressed the aberrant MFS in the hippocampus as evidenced by manganese enhanced MRI and Timm staining. This study demonstrated that the intravenous infusion of MSCs mitigated epileptogenesis, thus advancing MSCs as an effective approach for epilepsy in clinical practice.

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  • Development of new therapy with mesenchymal stem cell for reperfusion injury following reperfusion therapy

    Grant number：16K10730  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Honmou Osamu

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Reperfusion therapy with rtPA is the standard therapy for stroke. However, hemorrhagic complications can result. Intravenous infusion of MSCs provides therapeutic efficacy. One suggested mechanism is inhibition of endothelial dysfunction. Four groups were studied: 1) NS+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, 4) rtPA+MSCs. The MSC-treated groups (3,4) experienced a greater reduction in the incidence rate of intracerebral hemorrhage and hemorrhagic volume after tMCAO even if rtPA was received. Behavioral testing indicated that MSC-infused groups had greater improvement, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (2,4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups. Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined therapy MSCs and rtPA facilitated early behavioral recovery.

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  • Prevention of neointimal hyperplasia induced by an endovascular stent via intravenous infusion of mesenchymal stem cells

    Grant number：16K10731  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Katsuya Komatsu

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    In-stent restenosis causes recurrent ischemic events. Neointimal hyperplasia induced by an inflammatory response to the stent strut may be a possible mechanism of in-stent restenosis. Intravenous infusion of mesenchymal stem cells (MSCs) has been reported to show therapeutic efficacy for cerebral stroke presumably by an anti-inflammatory effect. This study aimed to determine whether MSCs can reduce or prevent neointimal hyperplasia induced by an endovascular stent. We deployed two types of stents using an animal model. Stents were implanted in the common carotid artery (CCA), and superficial cervical artery (SCA). Infused MSC immediately after deployment of stents prevented in-stent stenosis of CCA and SCA. Intravenous infusion of MSCs inhibited the inflammatory reaction to an implanted stent strut, and prevented progressive neointimal hyperplasia in the stented CCA and SCA. Thus, MSC treatment could attenuate the recurrence of cerebral ischemic events after stenting.

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  • Intravenous infusion of mesenchymal stem cells reduces erectile dysfunction following cavernous nerve injury in rats

    Grant number：16K11052  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    MATSUDA YOHEI

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Rats were randomized into two groups after electric CN injury. Intravenous infusion of mesenchymal stem cells (MSCs) or vehicle was performed three hours after electric CN injury. To assess erectile function, we measured the intracavernous pressure (ICP) at 4 weeks after MSC or vehicle infusion. Histological examinations were performed to investigate neuronal innervation and inhibition of smooth muscle atrophy. To investigate mRNA expression levels of neurotrophines in the major pelvic ganglia (MPG), real-time PCR was carried out. The reduction of ICP in the MSC group was significantly lower than in the vehicle group four weeks after infusions. The smooth muscle to collagen ratio in the MSC group was significantly higher than that in the vehicle group. GFP-MSCs were detected in the MPG and injured CN indicating homing of the cells to the MPG and injured CNs. BDNF and GDNF had expression levels in MPG significantly higher in the MSC group than in the vehicle group.

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  • 脳海綿状血管腫に対する分子標的療法の開発

    Grant number：16K10733  2016.4 - 2019.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    能代 将平, 佐々木 祐典, 鰐渕 昌彦, 三上 毅, 三國 信啓, 本望 修

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • Functional recovery following intravenous infusion of mesenchymal stem cells in experimental spinal cord injury

    Grant number：16K10794  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Sasaki Masanori

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Recent studies has demonstrated that remote responses in the brain, as well as local responses in the injured spinal cord, can be occurred following spinal cord injury (SCI). Intravenous infusion of mesenchymal stem cells (MSCs) has been shown to elicit functional recovery in SCI through local mechanisms. We studied brain response that might be associated with the functional improvements induced by the infused MSCs following SCI. Genomewide RNA profiling was conducted in the motor cortex of SCI rats at 3 days post infusion. Then, qRT-PCR revealed that the ‘‘behaviorally-associated differentially expressed genes (DEGs)’’ were identified by the Pearson’s correlation analysis with the behavioral function, suggesting that these genes may be related to the functional recovery after infused MSCs. These results suggested that the infused MSCs alter the gene expression signature in the brain and that these expression changes may contribute to the improved function.

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  • Restoration of cognitive impairment following intravenous infusion of mesenchymal stem cells in a rat model of cerebral small vessel disease

    Grant number：15K10312  2015.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Nakazaki Masahito, HONMOU Osamu

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Recently, intravenous mesenchymal stem cells (MSC) transplantation has been reported that greater therapeutic efficacy can be achieved via multiple mechanisms for various disorders. In this study, we aimed to investigate the effect of MSC transplantation in a rat model of vascular dementia by histological, MRI, and behavioral analysis. We used the Spontaneously hypertensive rats stroke-prone (SHRSP) with cognitive impairment. At week 21of age, transplantation of MSC was performed by intravenous injection. Compared with the vehicle group, the MSC infused group showed a significant improvement in cognitive function. The MRI demonstrated that the MSC infused group showed a significant reduction of brain atrophy compared to the vehicle group. The histological analysis also showed the volume of cerebral cortex and hippocampus were higher in MSC group than vehicle group. Collectively, intravenous infusion of MSCs might provide therapeutic efficacy in a rat model of vascular dementia.

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  • The use of material of human origin in the commercial framework

    Grant number：26670250  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    ISHINO MASAHO, HONMOU Osamu, MIZUTANI Shuki, SUGAWARA Katsura

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    Grant amount：\3770000 （ Direct Cost: \2900000 、 Indirect Cost：\870000 ）

    In this study, it is explored how in Japan allogenic tissues/cells for producing regenerative medicine can be constantly procured. One of the rare cases of procurement system, which is running in Japan, of human tissues for producing medicine is blood donation. This system is developed under public regime with constant education. However, in contrast to hematological drug, each cellular medicine requires different protocol from the step of collecting tissues, and therefore tissue collection establishments should be developed from private sector. In this study, it is concluded that designing system for defining the legal status of such tissue collection establishments is essential for the practical realization in Japan of regenerative medicine utilizing allogenic tissues/cells.

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  • Therapeutic Effects of Intravenous Infusion of MSCs in Hypoxic-Ischemic Encephalopathy Rat

    Grant number：26462168  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Sakai Takuro, HONMOU Osamu

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    We aimed to investigate the effect of mesenchymal stem cells (MSCs) transplantation in a rat model of neonatal hypoxic-ischemic encephalopathy (HIE) by histological, MRI, and behavioral analysis. At postnatal day 7, rats were underwent HI by left common carotid artery occlusion followed by 120 min hypoxia (8% oxygen). At postnatal day 10, transplantation of MSCs was performed by intravenous injection. Compared with the vehicle (control) group, the MSC infused group showed a significant improvement in athletic performance by the evaluation with the beam walk test. The MRI also demonstrated that the MSC infused group showed a significant reduction of the ischemic volume compared to the vehicle group. Collectively, intravenous infusion of MSCs might provide therapeutic efficacy in a rat model of HIE.

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  • INTRAVENOUS INFUSION OF MESENCHYMAL STEM CELLS PROMOTES FUNCTIONAL RECOVERY IN A MODEL OF CHRONIC SPINAL CORD INJURY

    Grant number：26462213  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Morita Tomonori, HONMOU Osamu

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    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    Intravenous infusion of mesenchymal stem cells (MSCs) derived from bone marrow improves behavioral function in rat models of acute spinal cord injury (SCI). In this study, MSCs were infused 10 weeks after the induction of a severe contusive SCI. Locomotor function was assessed until 20 weeks post-SCI. Motor recovery was greater in the MSC group with rapid improvement beginning in earlier post-infusion times than in the vehicle group. Blood spinal cord barrier (BSCB) integrity was assessed by the intravenous infusion of Evans Blue with quantitation of its leakage, and that was reduced in the MSC group. There was extensive remyelination around the lesion center and increased neovascularization/sprouting of the nerve fibers. These results indicate that the MSC therapy results in functional improvements that is associated with structural changes in the chronically injured spinal cord including stabilization of the BSCB, axonal sprouting/regeneration and remyelination.

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  • 骨髄幹細胞移植による海綿体神経の保護・再生と勃起機能の温存

    Grant number：25462516  2013.4 - 2016.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    高柳 明夫, 佐々木 祐典, 小林 皇, 本望 修

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    Grant amount：\5070000 （ Direct Cost: \3900000 、 Indirect Cost：\1170000 ）

    【目的】本研究では、前立腺全摘除術の特性を考慮し、海綿体神経(CN)損傷モデルを用いて、神経損傷前にMSCを静脈投与することが勃起機能の温存に寄与するかを検討した。また、投与した骨髄間葉系幹細胞（MSC）の動態を観察し、作用機序についての検討を行った。
    【方法】SDラット（雄、8週齢）のCNに機械的な損傷を加え、CN損傷モデルとした。勃起機能の評価として、CNを電気刺激して得られる海綿体内圧と動脈圧の比(ICP/AP)を用いた。正常ラットに対して、ICP/AP測定後に、ランダム化を行った。MSC群には1×106個（/1ml）のMSC、対照群にはDMEM (1ml)を経静脈的に投与し、その直後にCN損傷を作成した。損傷1時間および2週後にICP/APを測定し、勃起機能を評価した。PKH26を標識したMSC(PKH26-MSC)を用いて移植MSCの組織分布を評価した。また、骨盤神経節（MPG）でのGDNF、Neurturinの発現を定量リアルタイムPCR (qPCR)法で 解析した。
    【結果】神経損傷1時間後のICP/APは、両群ともに損傷前のICP/APに比べて有意な低下を認め(P＜0.01)、MSC群のICP/APは対照群に比べて有意に高かった(p＜0.05)。損傷2週後のICP/APもMSC群では対照群に比べて有意に高かった(p＜0.01)。移植したPKH26-MSCが、MPG、CNに分布することを確認した。qPCR法では、MSC群ではMPG中のGDNFおよびNeurturinの発現が対照群に比べて有意に亢進していた。(p＜0.01, p<0.05)
    【結論】MSCをCN損傷前に静脈投与することで、神経損傷後の勃起機能が温存された。投与されたMSCはMPGやCNに分布しており、神経栄養因子の発現が亢進することが神経保護作用を誘導する理由の一つであると推測された。

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  • Fundamental Researches for the Application of Human Small Hepatocytes in Clinical Treatment

    Grant number：25293289  2013.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HIRATA Koichi, MITAKA Toshihiro, MIZUGUCHI Toru, TANIGUCHI Naoki, ISHII Masayuki, HONMOU Osamu, MEGURO Makoto, KAWAMOTO Masaki, TATSUMI Hiroomi, ZENBUTSU Hitoshi

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    Grant amount：\18070000 （ Direct Cost: \13900000 、 Indirect Cost：\4170000 ）

    The researches for the clinical application of human small hepatocyte stem cells (hu-SHSC) for cell transplantation in liver resulted as follows. (1) The hu-SHSC isolation were stable, using the step-wise collagenase perfusion method and the Percoll○R gradient centrifugation method. To identify the specificity of hu-SHSC, histochemical examinations and molecular analysis were reffered. The cytological influence under several kinds of preservation intervals in freezed condition were analysed. Finally, it has been proven that the purification and preservation of hu-SHSC were steadied. (2) The possibility of artificial control on proliferation, differentiation and promotion in hepatic regeneration were satisfied. (3) The transplantation of hu-SHSC in rodent liver was succeeded in proliferation and differentiation. (4)No characteristics concerned to tumorigenicity of SHSC has been examined, but now is ongoing.
    SHSC may be a candidate as the donor cell in injured liver.

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  • Profile analysis of mesenchymal stem cell for cellular therapy

    Grant number：25462226  2013.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Honmou Osamu, Wanibuchi Masahiko, Sasaki Masanori, Mikami Takeshi, Kobayashi Masaki, Nakazaki Masahito, Sakai Takuro, Sasaki Yuichi, Suzuki Junpei, Morita Tomonori, Namioka Ai, Namioka Takahiro

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    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    Recent progress in regenerative medicine for injured neural tissue have revealed that greater therapeutic efficacy can be achieved by stem cell therapy via multiple mechanisms for various disorders. Especially, it has been suggested that mesenchymal stem cells (MSCs) derived from bone marrow may represent a potential source for organ regeneration. In this study, cell biological analyses were performed with MSCs from human and rat bone marrow using several molecular, biochemical and genetics approaches. Therapeutic efficacy by rat MSCs in vivo was also examined with rat stroke model.

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  • Characteristic analysis of mesenchymal stem cells for regenerative medicine

    Grant number：24592138  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    RIE Onodera, HONMOU Osamu, WANIBUCHI Masahiko, SASAKI Masanori, MIKAMI Takeshi, KOBAYASHI Masaki, NAKAZAKI Masahito, SAKAI Takurou, SASAKI Yuichi, SUZUKI Junpei, MORITA Tomonori

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    Grant amount：\5200000 （ Direct Cost: \4000000 、 Indirect Cost：\1200000 ）

    Recent advance in regenerative medicine have demonstrated that greater therapeutic efficacy can be obtained by stem cell therapy via multiple mechanisms compared to the standard therapies for various diseases. Especially, it has been suggested that bone marrow stem cells may represent an alternative source of neural progenitor cells for organ regeneration. Among bone marrow stem cells, much attention has been paid to mesenchymal stem cells (MSCs, also referred to as bone marrow stromal cells) because of their plasticity for differentiation into classical mesenchymal lineages, such as neuronal lineages. In this study, cell biological analyses were performed with MSCs from human and rat bone marrow using several molecular, biochemical and genetics approaches. Therapeutic efficacy with rat MSCs in vivo was also examined with rat stroke model.

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  • Basic reserach for developing a new therapy by transplantation of mesenchymal stem cells against neurodegenerative diseases

    Grant number：22390180  2010.4 - 2014.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    SHIMOHAMA Shun, HONMOU Osamu

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    Grant amount：\18330000 （ Direct Cost: \14100000 、 Indirect Cost：\4230000 ）

    To explore a novel therapy against Parkinson disease, we evaluated the therapeutic effects of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in 6-OHDA induced Parkinson disease model rats. Intravenous administration of hBM-MSCs inhibited methamphetamine-stimulated rotational behevior at 7, 14, 21 and 28 days after transplantation. Rats injected with hBM-MSCs displayed significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra compacta (SNpc). In contrast, the immunoreactivity of ionized calcium binding adaptor molecule 1 (Iba1) was markedly inhibited by intravenous admnistration of hBM-MSCs. The findings that hBM-MSCs attenuate 6-OHDA-induced dopaminergic neurodegeneration and glial activation raise the possibility that hBM-MSCs could be a novel therapeutic option to prevent Parkinson disease development.

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  • Therapeutic benefits of the genetically-engineering mesenchymal stem cells for sub-acute cerebral ischemia

    Grant number：20390388  2008 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HONMOU Osamu, HAMADA Hirofumi, HOUKIN Kiyohiro

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    Grant amount：\19240000 （ Direct Cost: \14800000 、 Indirect Cost：\4440000 ）

    We have reported that transplantation of bone marrow stem cells has demonstrated therapeutic efficacy in animal models of acute cerebral ischemia. In the present study, we transplanted bone marrow stem cells into middle cerebral artery occlusion model rats to study their potential therapeutic benefit in the subacute phase. This work demonstrates that highly purified bone marrow stem cells are neuroprotective and angeigenetic in subacute cerebral ischemia models.

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  • Therapeutic benefits of intravenous administration of genetically-engineering mesenchymal stem cells on spinal cord injury

    Grant number：20591717  2008 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    NONAKA Tadashi, HOUKIN Kiyohiro, HONMOU Osamu

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Local injection of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). Systemic delivery of MSCs results in therapeutic benefits in a number of central nervous system disorders. In the present study we intravenously administered MSCs derived from bone marrow to study their potential therapeutic effect in a contusive SCI model in the rat. Light microscopic examination revealed that cavitation in the contused spinal cords was less in the MSC-treated rats. Functional outcome was greater in the MSC-treated groups than in sham controls with greatest improvement in the earlier post-contusion infusion times. BDNF-hypersecreting MSC enhanced the therapeutic benefits of MSC on SCI. The availability of autologous MSCs in large number and the potential for systemically delivering cells to target lesion areas without neurosurgical intervention suggests the potential utility of intravenous cell delivery as a prospective therapeutic approach in SCI.

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  • Elucidation of the role of intramedullary microcirculation in the pathogenesis of syringomyelia and the possibility of a new treatment

    Grant number：19591692  2007 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    KOYANAGI Izumi, HOUKIN Kiyohiro, AKIYAMA Yukinori, HONMOU Osamu

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    Pathogenesis of syringomyelia was studied using experimental models and radiological analysis of clinical cases. The results indicate that the dynamics of extracellular fluid and intramedullary microcirculation plays an important role in development of syringomyelia. In syringomyelia, the increased extracellular fluid state was present around the central canal and the syrinx and spread centrifugally. Such interstitial edema disappeared after treatment of the syrinx. Disturbed absorption of the extracellular fluid through the intramedullary venous system will be the primary mechanism in the pathogenesis of syringomyelia.

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  • Therapeutic benefits of intravenous administration of mesenchymal stem cells on spinal cord injury-Contribution of Diacylglycerol to neurogenesis-

    Grant number：19591691  2007 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    MURAKAMI Tomohiro, HOUKIN Kiyohiro, HONMOU Osamu

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    Local injection of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). Systemic delivery of MSCs results in therapeutic benefits in a number of central nervous system disorders. In the present study we intravenously administered rat MSCs derived from bone marrow to study their potential therapeutic effect in a contusive SCI model in the rat. MSCs were systemically delivered at varied time points (6 hours to 28 days after SCI). The spinal cords were examined histologically six weeks after SCI. Stereological quantification was performed on the spinal cords to determine donor cell (MSCs transduced with the LacZ gene) density in the lesions. Light microscopic examination revealed that cavitation in the contused spinal cords was less in the MSC-treated rats. A limited number of cells derived from MSCs (LacZ^+) in the injury site expressed neural or glial markers. Functional outcome measurements using the Basso-Beattie-Bresnehan (BBB) score were performed periodically up to 6 weeks post-SCI. Locomotor recovery improvement was greater in the MSC-treated groups than in sham controls with greatest improvement in the earlier post-contusion infusion times. The availability of autologous MSCs in large number and the potential for systemically delivering cells to target lesion areas without neurosurgical intervention suggests the potential utility of intravenous cell delivery as a prospective therapeutic approach in SCI.

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  • A genetically-engineering bone marrow stem cell therapy for stroke

    Grant number：16390414  2004 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HONMOU Osamu, HOUKIN Kiyohiro, HAMADA Hirofumi

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    Grant amount：\15250000 （ Direct Cost: \14200000 、 Indirect Cost：\1050000 ）

    Introduction : We have reported that transplantation of bone marrow cells has demonstrated therapeutic efficacy in animal models of cerebral ischemia. In the present study, we transplanted genetically-engineering bone marrow stem cells into middle cerebral artery occlusion model rats to study their potential therapeutic benefit.
    Methdos : We have made five genetically-engineering bone marrow stem cells, 1) to immortalize the stem cells with hTERT gene, 2) to promote the neurotrophic effects with BDNF gene, 3) to promote the neurotrophic effects with GDNF gene, 4) to promote the angiogenetic effects with Ang-1 gene, 5) to promote the angiogenetic effects with P1GF gene. Lesion size was assessed using MR imaging and spectroscopy, and histological methods.
    Results : Transplantation of genetically-engineering bone marrow stem cells reduced lesion volume. The reduction of lesion size could be assessed in vivo with MRI and was correlated with subsequent histological examination of the brain.
    Conclusion : This work demonstrates that highly purified genetically-engineering bone marrow stem cells are neuroprotective and angeigenetic in cerebral ischemia models. Thus, a highly purified, expanded, and genetically-engineered cellular component of bone marrow has demonstrated the therapeutic benefits in cerebral ischemia.

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  • Therapeutic benefits of mesenchymal stem cells derived from peripheral blood on spinal cord injury

    Grant number：16591450  2004 - 2006

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    NONAKA Tadashi, HONMOU Osamu, HOUKIN Kiyohiro

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    Grant amount：\3500000 （ Direct Cost: \3500000 ）

    Intravenous injection of mesenchymal stem cells (MSCs) prepared from adult bone marrow (BMSCs) has been reported to ameliorate functional deficits in several CNS diseases in experimental animal models. Although bone marrow was enriched in MSCs, MSC-like multipotent precursor cells (PMSCs) have also been suggested to exist in peripheral blood. These cells will grow to confluency in appropriate culture conditions as flattened fibroblast-like cells. Despite the fact that the stem/precursor cells in peripheral blood is widely used for reconstruction in the hemopoietic system, it remains unclear whether peripheral blood-derived plastic-adherent stem/precursor cells (PMSCs) have potential utility for CNS diseases.
    To compare the potential of PMSCs and BMSCs for neural differentiation in vitro, BMSCs and PMSCs were prepared from the adult rat and expanded in culture. Although the growth rate of PMSCs was less than BMSCs, immunocy ochemical and RT-PCR analyses indicated that both MSC types were successfully induced to nestin-positive neurospheres in the presence of EGF and bFGF. After withdrawal of the mitogens, these cells could differentiate into neurofilament-positive neurons or GFAP-positive glia.
    To test the hypothesis that treatment with PMSCs may have a therapeutic benefit in spinal cord injury, we compared the efficacy of BMSCs and PMSCs. Rat BMSCs and PMSCs were prepared in culture and injected into the injured spinal cord in the rats. Lesion was assessed 3 weeks after injury using MR imaging and histology. Functional outcome was also assessed. Both BMSCs and PMSCs treated groups had functional improvement compared to the control group. The therapeutic benefits of both MSC-treated groups were similar. These data suggest that PMSCs derived from peripheral blood could be an important cell source of cell therapy for spinal cord injury.

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  • 心肺停止・蘇生後脳症におけるアポトーシス検出画像の開発

    Grant number：16659393  2004 - 2005

    日本学術振興会  科学研究費助成事業  萌芽研究

    寶金 清博, 小柳 泉, 本望 修, 三上 毅, 鹿野 恒

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    Grant amount：\3300000 （ Direct Cost: \3300000 ）

    本研究では、心肺停止後の蘇生脳に起こる脳の変化を画像でとられ、その病理所見との比較を行うことで、予後診断へ役立てることを主目的としている。そこで、まず、高度脳虚血-再灌流モデルにおける、実験用高磁場MRIの検討を行った。また、臨床例における、心肺停止後の蘇生脳の画像、代謝を検討した。さらに、ラット心肺停止モデルにおいて、実験用高磁場MRIと早期病理診断(アポトーシス検出)との比較解析を行った。
    1.実験高度脳虚血-再灌流モデルのMRI
    ラットの心肺停止後の蘇生後脳の状態をsimulationするモデルとして、ラットの中大脳動脈閉塞・再灌流モデルを用いて、高磁場(7テスラー)のMRI装置を用いて、画像撮像を行った。その結果、再灌流後、fractional anisotrophy image(FA画像)において、再灌流脳において異方性が早期に失われ、その後、そのanisotrophyを失った範囲において、梗塞の出現と慢性期において萎縮が進行することが示された。また、この部位において、magnetic resonance spectroscopy(MRS)を行うと、乳酸の出現とさらに正常状態では見られないlipidの出現が見られた。
    2.人における蘇生後脳症のMRI・MRS
    心肺停止後の蘇生後脳症で、予後不良例、良好例における、拡散強調画像、MRSの差異を検討した結果、予後良好例では、実験と同様に、anisotrophyが保持され、嫌気性代謝のマーカーである乳酸の出現が認められなかった。これに対して、予後不良例では、早期から異方性が喪失し、乳酸が出現することが示された。
    3.ラット心肺停止モデルにおける実験用高磁場MRIと早期病理診断(アポトーシス検出)との比較解析
    ラットを用いて、心肺を完全停止(9分間)後、蘇生させるモデルを作成した。同モデルでは、発症早期において実験用高磁場MRI上、異常信号を捕らえることが出でき、また、早期病理診断では神経細胞がアポトーシスに陥っていることを確認している。以上より、心肺停止後の蘇生脳に起こる脳の病態生理的変化と、発症早期のMRI画像所見が相関することを突き止め、予後診断とともに、早期治療の効果判定に有用となると思われた。

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  • Development of the Treatment of Amyotrophic Lateral Sclerosis (ALS) with Neural Stem Cells

    Grant number：14570598  2002 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    NAGANO Isao, ABE Koji, HONMOU Osamu

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    Grant amount：\3000000 （ Direct Cost: \3000000 ）

    At first, we examined the induction of vascular endothelial growth factor (VEGF) in the G93A SOD1-mutant mice exposed to systemic hypoxia. Baseline expression of VEGF was increased in the SOD1-mutant mice compared with wild-type littermates. VEGF expression in the mutant mice was hardly induced by hypoxia, in contrast to the wild-type littermates where approximately nine-fold increase in VEGF expression was observed, indicating that the response of VEGF to hypoxia is impaired in the SOD1-mutant mice. We next investigated whether reduction of Flk-1, one of VEGF receptors, could induce motor neuron loss by inhibiting the Flk-1 expression using antisense oligodeoxynucleotides (AS-ODNs). Intrathecal infusion of AS-ODNs for 7 days suppressed almost completely Flk-1 expression in the lumbar segment, and was followed by a hypoxic challenge for 1 hour that was repeated for 7 more days. We observed that reduced Flk-1 expression and hypoxic challenge for 7 days resulted in 〜50% loss of motor neurons, in which the activation of Akt and ERK, that is increased levels of phosphorylated-Akt and of phosphorylated-ERK by hypoxia, was markedly inhibited. These results suggest that VEGF exerts its protective effect on motor neurons against hypoxia-induced toxicity by the Flk-1 receptor.
    To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, the G93A SOD1-mutant mice were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Next, we performed a double blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS. We found that the intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects.

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  • Targeted gene therapy for brain tumor

    Grant number：14370440  2002 - 2003

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HAMADA Hirofumi, SASAKI Katsunori, HONMOU Osamu

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    Grant amount：\14900000 （ Direct Cost: \14900000 ）

    The prognosis of patients with malignant glioma is extremely poor, despite the extensive surgical treatment that they receive and recent improvements in adjuvant radio-and chemotherapy. In the present study, we propose the use of gene-modified mesenchymal stem cells(MSCs) as a new tool for gene therapy of malignant brain neoplasms. Primary MSCs isolated from Fischer 344 rats possessed excellent migratory ability and exerted inhibitory effects on the proliferation of 9L glioma cells in vitro. We also confirmed the migratory capacity of MSCs in vivo and showed that when they were inoculated into the contralateral hemisphere, they migrated towards 9L glioma cells through the corpus callosum. MSCs implanted directly into the tumor localized mainly at the border between the 9L tumor cells and normal brain parenchyma, and also infiltrated into the tumor bed. Intratumoral injection of MSCs alone caused significant inhibition of 9L tumor growth and increased the survival of 9L glioma-bearing rats.
    Due to the lack of the receptor(CAR) on MSCs, the efficiency of gene transfer into MSCs by the adenoviral vector(Adv) with the wild-type AdS fiber(Adv-F/wt) was very poor. In clear contrast, nearly 100% genetic transduction of MSCs was achieved using the integrin-targeting fiber-mutant Adv-F/RGD, which possesses a CDCRGDCFC peptide motif at the HI-loop of the fiber knob. Gene-modification of MSCs by infection with an adenoviral vector encoding human interleukin-2(IL2) clearly augmented the antitumor effect and further prolonged the survival of tumor-bearing rats. Thus, gene therapy employing MSCs as a targeting vehicle would be promising as a new therapeutic approach for refractory, invasive brain tumors.

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  • Functional recovery of the cerebral tissue following transplantation of the genetically-engineering bone marrow stem cells.

    Grant number：14370442  2002 - 2003

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HONMOU Osamu, HAMADA Hirofumi, HOUKIN Kiyohiro

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    Grant amount：\13900000 （ Direct Cost: \13900000 ）

    Introduction : We have reported that transplantation of bone marrow cells has demonstrated therapeutic efficacy in animal models of cerebral ischemia and demyelination. In the present study, we transplanted genetically-engineering bone marrow stem cells into both middle cerebral artery occlusion model rats and brain tumor model rats, to study their potential therapeutic benefit.
    Methdos : We have made three genetically-engineering bone marrow stem cells, 1)to immortalize the stem cells with hTERT gene, 2)to promote the neurotrophic effects with BDNF gene, 3)to promote the anti-tumor effect with IL=2 gene. Lesion size was assessed using MR imaging and spectroscopy, and histological methods.
    Results : Transplantation of genetically-engineering bone marrow stem cells reduced lesion volume. The reduction of lesion size could be assessed in vivo with MRI and MRS and was correlated with subsequent histological examination of the brain.
    Conclusion : This work demonstrates that highly purified genetically-engineering bone marrow stem cells are neuroprotective in cerebral ischemia models. Also, these cells showed the tremendous anti-tumor effects. Thus, a highly purified, expanded, and genetically-engineered cellular component of bone marrow has demonstrated the therapeutic benefits in both cerebral ischemia and brain tumor.

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  • 腫瘍の特異的標的化を目指した遺伝子治療法の開発

    Grant number：12217123  2000 - 2004

    日本学術振興会  科学研究費助成事業  特定領域研究

    濱田 洋文, 加藤 和則, 中村 公則, 本望 修, 伊藤 克礼, 佐々木 勝則

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    Grant amount：\94800000 （ Direct Cost: \94800000 ）

    腫瘍に対する選択的標的化の候補分子を探索するために、抗体のFcドメインに結合するProtein AのZ33モチーフをAd5ファイバーのHIループに持つAdv-FZ33アデノウイルスを作成した。CARをほとんど発現しないヒト膵癌細胞AsPc1やヒトメラノーマ細胞A375に対する遺伝子導入効率をEGFPないしb-gal遺伝子発現で測定した。AsPc1やA375に発現する表面分子(CD29、CD54など)に対する抗体を付着させたAdv-FZ33による遺伝子導入・遺伝子発現は、コントロール(抗体の非存在下またはコントロールIgG併用でのAdv-FZ33、ならびに野生型Ad5ファイバーAdv-Fwtのウイルス)による遺伝子導入・発現の数十倍に増強できた。また、ErbB2を高発現するヒト卵巣癌細胞(SK-OV3など)への遺伝子導入は、ErbB2抗体の併用により、選択的に著明に(EGFP遺伝子導入細胞%で、5%から90%へ)増強できた。腫瘍細胞とZ33アデノウイルスとを架橋することによって遺伝子導入効率が高まるモノクローナル抗体をスクリーニングすることにより、腫瘍細胞に対して標的化の可能な表面分子と抗体の組み合わせの探索を開始している。先行しているヒト膵癌を標的化できる新規抗体作製のプロジェクトでは、すでに4種類の抗体産生ハイブリドーマが樹立されている。このうちの一つクローンA^*によって得られるモノクローナル抗体は、AdvFZ33アデノウイルスの膵癌細胞AsPc1への遺伝子導入効率を、非常に強く(200倍)増強し、有望である。

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  • Functional recovery of the cerebral infarction following transplantation of the genetically-engineering human neural stem cells

    Grant number：12470295  2000 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HONMOU Osamu, UEDE Teiji

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    Grant amount：\16200000 （ Direct Cost: \16200000 ）

    Introduction: Although it has generally been assumed that the adult brain is incapable of significant self-repair because of a lack of neurogenesis in the adult mammalian central nervous system (CNS), several studies have reported that the adult mammalian brain harbors neural stem cells that retain the potential for both neural production and differentiation in experimental animal models. These findings offer the prospect of the presence of neural precursors in the adult human brain. The objective of this study was to identify neural stem cells in the adult human CNS and study whether they repair the ischemic brain.
    Methdos: Clonal neural stem cells derived from adult human brain were established in vitro. They were genetically marked with LacZ gene and was transplanted into the ischemic brain of the experimental animal. It was investigated if neural tissue reconstruction occurred following transplantation.
    Results: Single-cell clonal analysis demonstrated self-renewing and multipotential properties of neural stem cells derived from the adult human brain in vitro. Histological examination of the ischemic lesion following transplantation revealed that the transplanted human cells reconstructed the neural tissue. The transplanted stem cell in the contra-lateral hemisphere also migrated into the ischemic lesion of the another hemisphere, and repaired the damaged brain following ischemic stress. The electrophysiological and behavior studies also proved the functional recovery of the ischemic model animals following the human neural stem cell transplantation.
    Conclusion: Adult human brain harbors neural stem cells that retain the potential for both neural production and differentiation. Transplantation of clonal neural stem cells derived from adult human brain repaired the ischemic neural tissue in the mammalian adult CNS.

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  • ヒト神経幹細胞の移植による中枢神経系疾患の機能回復

    Grant number：11770765  1999 - 2000

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    本望 修

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    Grant amount：\2300000 （ Direct Cost: \2300000 ）

    当該研究計画はヒト神経幹細胞の成人脳における存在確認、局在、抽出・培養、脳内への移植療法の検討を主題とし、損傷を受けた神経回路の再構築を試みるものであった。成人脳における局在の解析、抽出・培養方法の確立、脱髄疾患・虚血性疾患への移植実験は昨年までの研究ですでに達成されている。本年度は以下の研究結果を得た。
    1:ヒト神経幹細胞の外傷モデルへの移植:ヒト神経幹細胞を免疫抑制下の外傷モデル(ラット除皮質モデル)へ移植し、1-3週後に組織学的解析を行なった結果、同部位にヒト神経幹細胞が生着、神経細胞やグリア細胞へと分化し、神経組織を再構築することが確認された。また、ホスト正常脳内へと遊走している所見、および損傷部位より正常脳内へ神経突起を伸ばしている様子も観察された。さらに、損傷部位と正常神経組織との移行部においても瘢痕組織の形成や腫瘍性の増殖は全く示さず、両領域間でスムーズな組織移行が観察された。
    2:神経栄養因子で分化を誘導した。神経幹細胞は神経栄養因子を使用しなくてもmitogenの添加を中止するだけで分化を開始し、約半数はneuronになり、また約40%はastrocyteへと分化した。また,ごく少数であるがoligodendrocyteへの分化も認められ、神経系の主要3系細胞に分化することが確認された。一方、神経栄養因子の添加では、さらに選択的な分化を誘導することが可能でった。例えば、PDGFを添加した群では,neuron細胞の比率が多くなり,astrocyteの割合は減少する。同様に、CNTF添加群では、グリア系細胞への分化が促進された。
    神経幹細胞から分化させた神経細胞の機能解析を電気生理学的に検討すると、分化誘導後、約4週間で活動電位を発するようになり、同時に、神経伝達物質に対する反応性も示した。また、免疫細胞学的解析でも神経伝達物質とその受容体の発現が認められた。さらに、細胞間のシナプス伝達も電気生理学的に確認され、同所見は電子顕微鏡での超微細構造の観察でも確認された。これらの結果より、成人脳由来の神経幹細胞は、移植後、ホストの神経組織内でも機能的に分化し、神経ネットワークを再建でき得ると推測された。
    3:Major Histocompatibility Complex(MHC)の移植免疫への影響を検討:神経幹細胞はホスト神経組織へ移植されるとMHC抗原を呈することが判明し、移植療法において拒絶反応を考慮せざるを得ないことが確認された。さらに、MHC class I and class II knock-out由来の神経幹細胞をドナー細胞とした実験でも、同抗原提示が拒絶反応に大きく関与していることが判明した。
    以上のように、補助金は補助条件に従って、非常に有用に使用されている。

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  • Functional recovery of the demyelinated diseases following transplantation of the genetically-engineering cells.

    Grant number：09671434  1997 - 1999

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    UEDA Teiji, HONMOU Osamu

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    Grant amount：\3600000 （ Direct Cost: \3600000 ）

    It has generally been assumed that the adult central nervous system (CNS) is incapable of significant self-repair because of a lack of neurogenesis in the adult mammalian CNS. Although we have reported that remyelination of demyelinated CNS axons occurs following transplantation of exogenous glial cells in the animal models, it is still unclear whether transplantation of myelin-forming cell derived from adult humans can remyelinate the demyelinated axons and restore the conduction properties in the adult CNS. To examine this issue, the dorsal columns of the adult rat spinal cord were demyelinated by X-irradiation and intraspinal infections of ethidium bromide. Cell suspensions of myelin-forming cells such as Schwann cells, olfactory ensheathing cells, neural stem cells derived from adult humans were infected into the glial-free lesion site. Light and electron microscopic examination of the dorsal columns revealed cells engaging and myelinating axons in the demyelinated regions 21 days after transplantation. In addition, in situ hybridization study with COT-1 DNA probe which is specific to human DNA indicated that the new myelin was formed by the human cells. The dorsal columns were removed and maintained in an in vitro recording chamber; conduction properties were studied using field potential recording techniques. The demyelinated axons exhibited conduction slowing and block, and a reduction in their ability to follow high frequency stimulation. Axons remyelinated by transplantation of myelin-forming cells derived from adult human exhibited restoration of conduction through the lesion, with re-establishment of normal conduction velocity. The axons remyelinated following transplantation showed enhanced impulse recovery to paired pulse stimulation and greater frequency-following capability as compared to both demyelinated axons. These results demonstrate the functional repair of demyelinated axons in the adult CNS by transplantation of myelin-forming cells derived from adult human.

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  • 側頭葉てんかんに対する遺伝子療法-海馬へのGABA産生細胞移植-

    Grant number：09771051  1997 - 1998

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    本望 修

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    Grant amount：\2200000 （ Direct Cost: \2200000 ）

    昨年度は、GABA合成酵素であるglutamic acid decarboxylase(GAD)のhuman cDNA expression vector(pC1-neo-GAD)を作製し、lipofection方法にてhuman astrocyteへ導入後、発現をimmunocytochemistoryで確認した。さらに、それに伴う細胞内GABAの上昇をimmunocytochemistoryで確認した。
    今年度はGAD mRNAの発現をin situ hybridizationにより確認した。さらに、限界希釈法にて細胞内GABA濃度が十分高められた細胞を選別・clonal expansionし、highly expressed cell lineを確立した。また、組胞内GABA濃度の上昇はHPCLによっても確かめた。
    われわれは、Nipecotic acid(NPA)にはGABA transporterのreverse operationにより細胞内free-GABAを細胞外に放出させる作用があることを以前より提唱しており、この作用を利用して、細胞内free-GABAレベルを間接的に評価してきた。今回の研究でも上記に得られた細胞に対するwhole-cell voltage clamp in vitro下におけるNPAのmicro-applicationによるGABA current(Cl^- current)の測定により、細胞のGABAの含有量とGABA放出能の測定を行なった結果、human GAD遺伝子導入細胞で著名なGABA currentの上昇を認めた。現在、上記細胞をラット脳内に移植し、in vivoにおけるGABA放出能の測定と抗痙攣作用の検討を行なっている。
    以上のように、補助金は補助条件に従って非常に有効に使用されている。

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