Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2024.04

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  Now

  札幌医科大学   医学部附属再生医療学研究所 神経再生医療学部門  

• 2024.04

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  Now

  Yale University   School of Medicine  

• 2022.09

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  2024.04

  Yale University   Associate Research Scientist

• 2018.09

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  2021.08

  Yale University   Postdoctoral Associate

• 2013.04

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  2018.08

  Sapporo Medical University  

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Neuroscience - general  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Yale　University   School of Medicine  

• Sapporo Medical University   School of Medicine   特任助教  

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Human mesenchymal stem-derived extracellular vesicles improve body growth and motor function following severe spinal cord injury in rat.

  Masahito Nakazaki, Karen L Lankford, Hideaki Yamamoto, Yoshiyuki Mae, Jeffery D Kocsis

  Clinical and translational medicine   13 ( 6 ) e1284  2023.06  [International journal]

  Authorship：   Lead author

  　View Summary

  BACKGROUND: Spinal cord injury (SCI) in young adults leads to severe sensorimotor disabilities as well as slowing of growth. Systemic pro-inflammatory cytokines are associated with growth failure and muscle wasting. Here we investigated whether intravenous (IV) delivery of small extracellular vesicles (sEVs) derived from human mesenchymal stem/stromal cells (MSC) has therapeutic effects on body growth and motor recovery and can modulate inflammatory cytokines following severe SCI in young adult rats. METHODS: Contusional SCI rats were randomized into three different treatment groups (human and rat MSC-sEVs and a PBS group) on day 7 post-SCI. Functional motor recovery and body growth were assessed weekly until day 70 post-SCI. Trafficking of sEVs after IV infusions in vivo, the uptake of sEVs in vitro, macrophage phenotype at the lesion and cytokine levels at the lesion, liver and systemic circulation were also evaluated. RESULTS: An IV delivery of both human and rat MSC-sEVs improved functional motor recovery after SCI and restored normal body growth in young adult SCI rats, indicating a broad therapeutic benefit of MSC-sEVs and a lack of species specificity for these effects. Human MSC-sEVs were selectively taken up by M2 macrophages in vivo and in vitro, consistent with our previous observations of rat MSC-sEV uptake. Furthermore, the infusion of human or rat MSC-sEVs resulted in an increase in the proportion of M2 macrophages and a decrease in the production of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 at the injury site, as well as a reduction in systemic serum levels of TNF-α and IL-6 and an increase in growth hormone receptors and IGF-1 levels in the liver. CONCLUSIONS: Both human and rat MSC-sEVs promote the recovery of body growth and motor function after SCI in young adult rats possibly via the cytokine modulation of growth-related hormonal pathways. Thus, MSC-sEVs affect both metabolic and neurological deficits in SCI.

  DOI PubMed

• Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF-β upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury.

  Masahito Nakazaki, Tomonori Morita, Karen L Lankford, Philip W Askenase, Jeffery D Kocsis

  Journal of extracellular vesicles   10 ( 11 ) e12137  2021.09  [International journal]

  Authorship：   Lead author

  　View Summary

  Intravenous (IV) infusion of bone marrow-derived mesenchymal stem/stromal cells (MSCs) stabilizes the blood-spinal cord barrier (BSCB) and improves functional recovery in experimental models of spinal cord injury (SCI). Although IV delivered MSCs do not traffic to the injury site, IV delivered small extracellular vesicles (sEVs) derived from MSCs (MSC-sEVs) do and are taken up by a subset of M2 macrophages. To test whether sEVs released by MSCs are responsible for the therapeutic effects of MSCs, we tracked sEVs produced by IV delivered DiR-labelled MSCs (DiR-MSCs) after transplantation into SCI rats. We found that sEVs were released by MSCs in vivo, trafficked to the injury site, associated specifically with M2 macrophages and co-localized with exosome markers. Furthermore, while a single MSC injection was sufficient to improve locomotor recovery, fractionated dosing of MSC-sEVs over 3 days (F-sEVs) was required to achieve similar therapeutic effects. Infusion of F-sEVs mimicked the effects of single dose MSC infusion on multiple parameters including: increased expression of M2 macrophage markers, upregulation of transforming growth factor-beta (TGF-β), TGF-β receptors and tight junction proteins, and reduction in BSCB permeability. These data suggest that release of sEVs by MSCs over time induces a cascade of cellular responses leading to improved functional recovery.

  DOI PubMed

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

  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  2021.04  [International journal]

  　View Summary

  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 PubMed

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

  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  2019.04  [Refereed]  [International journal]

  Authorship：   Lead author

  　View Summary

  Cerebral small vessel disease (CSVD) is not only a cause of vascular dementia (VD) but also a contributing factor to Alzheimer's disease (AD). The essential pathological feature of CSVD is the disruption of blood-brain barrier (BBB). Dysfunction of BBB due to degeneration of both endothelial cells and pericytes in capillaries leads to neuronal damage and progressive brain atrophy. Moreover, deterioration of amyloid-β (Aβ) clearance due to the failure of the transvascular BBB transport system results in accumulation of Aβ in the brain. Intravenous infusion of mesenchymal stem cells (MSCs) elicits functional recovery in experimental models including stroke and spinal cord injury. One effect of MSCs is to restore disrupted BBB through remodeling of microvasculature. Using spontaneously hypertensive rats (stroke-prone) with impaired cognitive function as a CSVD model, we have shown that infused MSCs has a therapeutic effect for cognitive function. Restoration of BBB function via remodeling of microvasculature and inhibition of Aβ accumulation could inhibit progressive brain atrophy and lead to restore cognitive dysfunction. Gene expression analysis indicated that infused MSCs activates both transforming growth factor-β and angiopoietin 1 signaling pathways and promotes the remodeling of microvasculature. Thus, infused MSCs may represent a novel therapy for both VD and AD.

  DOI PubMed

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

  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 ( Journal of Neurosurgery Publishing Group ({JNSPG}) )  127 ( 4 ) 1 - 10  2017.01  [Refereed]  [International journal]

  Authorship：   Lead author

  　View Summary

  OBJECTIVE Reperfusion therapy with intravenous recombinant tissue plasminogen activator (rtPA) is the standard of care for acute ischemic stroke. However, hemorrhagic complications can result. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in experimental stroke models. One suggested therapeutic mechanism is inhibition of vascular endothelial dysfunction. The objective of this study was to determine whether MSCs suppress hemorrhagic events after rtPA therapy in the acute phase of transient middle cerebral artery occlusion (tMCAO) in rats. METHODS After induction of tMCAO, 4 groups were studied: 1) normal saline [NSI+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, and 4) rtPA+MSCs. The incidence rate of intracerebral hemorrhage, both hemorrhagic and ischemic volume, and behavioral performance were examined. Matrix metalloproteinase-9 (MMP-9) levels in the brain were assessed with zymography. Quantitative analysis of regional cerebral blood flow (rCBF) was performed to assess hemodynamic change in the ischemic lesion. RESULTS The MSC-treated groups (Groups 3 and 4) experienced a greater reduction in the incidence rate of intracerebral hemorrhage and hemorrhagic volume 1 day after tMCAO even if rtPA was received. The application of rtPA enhanced activation of MMP-9, but MSCs inhibited MMP-9 activation. Behavioral testing indicated that both MSC-infused groups had greater improvement than non-MSC groups had, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (Groups 2 and 4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups. CONCLUSIONS Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined therapy of infused MSCs after rtPA therapy facilitated early behavioral recovery.

  DOI PubMed

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 脳梗塞に対する血栓回収療法後の骨髄間葉系幹細胞による細胞治療

  中崎公仁, 佐々木祐典, 佐々木祐典, 佐々木優子, 岡真一, 浪岡隆洋, 浪岡愛, KOCSIS Jeffery, 本望修, 本望修

  脳血管内治療(Web) ( (NPO)日本脳神経血管内治療学会 )  1 ( Supplement ) S221(J‐STAGE) - S221  2016.11

  J-GLOBAL

• Regenerative therapy using autologous mesenchymal stem cell for cerebral ischemia

  中﨑 公仁, 岡 真一, 浪岡 愛

  再生医療 : 日本再生医療学会雑誌 ( メディカルレビュー社 )  13 ( 3 ) 304 - 308  2014.08

  CiNii

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

  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  2018.05  [Refereed]  [International journal]

  　View Summary

  © 2018 Elsevier B.V. Systemic administration of mesenchymal stem cells (MSCs) following cerebral infarction exerts functional improvements. Previous research has suggested potential therapeutic mechanisms that promote neuroprotection and synaptogenesis. These include secretion of neurotrophic factors, remodeling of neural circuits, restoration of the blood brain barrier, reduction of inflammatory infiltration and demyelination, and elevation of trophic factors. In addition to these mechanisms, we hypothesized that restored interhemispheric bilateral motor cortex connectivity might be an additional mechanism of functional recovery. In the present study, we have shown, with both MRI diffusion tensor imaging (DTI) and neuroanatomical tracing techniques using an adeno-associated virus (AAV) expressing GFP, that there was anatomical restoration of cortical interhemispheric connections through the corpus callosum after intravenous infusion of MSCs in a rat middle cerebral artery occlusion (MCAO) stroke model. Moreover, the degree of connectivity was greater in the MSC-treated group than in the vehicle-infused group. In accordance, both the thickness of corpus callosum and synaptic puncta in the contralateral (non-infarcted) motor cortex connected to the corpus callosum were greater in the MSC-treated group than in the vehicle group. Together, these results suggest that distinct preservation of interhemispheric cortical connections through corpus callosum was promoted by intravenous infusion of MSCs. This anatomical preservation of the motor cortex in the contralateral hemisphere may contribute to functional improvements following MSC therapy for cerebral stroke.

  DOI PubMed

• 脳小血管病と急性再開通治療3ヵ月後の臨床転帰との関係

  中崎 公仁, 野中 雅, 野村 達史, 恩田 敏之, 米増 保之, 高橋 明, 橋本 祐治, 本田 修, 佐々木 祐典, 大坊 雅彦, 本望 修

  脳血管内治療 ( (NPO)日本脳神経血管内治療学会 )  2 ( Suppl. ) S170 - S170  2017.11

• 脳小血管病と緊急血栓回収療法の臨床転帰との関係

  中崎公仁, 野中雅, 野村達史, 恩田敏之, 野中雅, 野村達史, 恩田敏之, 米増保之, 高橋明, 橋本祐治, 本田修, 佐々木祐典, 大坊雅彦, 本望修

  脳循環代謝(Web) ( 日本脳循環代謝学会 )  29 ( 1 ) 159 - 159  2017.11

  J-GLOBAL

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Industrial Property Rights 【 display / non-display 】

Industrial Property Rights 【 display / non-display 】

• 脳梗塞の治療用医薬

  本望 修, 中崎 公仁, 佐々木 祐典, 佐々木 優子, 岡 真一

  Patent

  J-GLOBAL

• 寿命延長剤

  本望 修, 佐々木 祐典, 佐々木 優子, 前澤理恵, 岡 真一, 中崎 公仁

  Patent

• ステント内再狭窄の予防のための医薬組成物

  本望 修, 佐々木 祐典, 佐々木 優子, 前澤理恵, 岡 真一, 中崎 公仁

  Patent

• 筋萎縮性側索硬化症の治療用医薬組成物

  本望 修, 佐々木 祐典, 佐々木 優子, 前澤理恵, 岡 真一, 中崎 公仁

  Patent

• シナプス形成剤

  本望 修, 佐々木 祐典, 佐々木 優子, 前澤理恵, 岡 真一, 中崎 公仁

  Patent

Awards 【 display / non-display 】

Awards 【 display / non-display 】

• 上原財団海外留学助成 リサーチフェローシップ

  2018.03  

• 日本脳卒中学会 最優秀口演賞

  2018.03  

• ヨーロッパ脳卒中学会 Young Investigator Award

  2009.05  

• 日本脳卒中学会 優秀ポスター賞

  2013.03  

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

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

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2015.04

  -

  2018.03

   

  Nakazaki Masahito, HONMOU Osamu

  　View Summary

  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.

• 骨髄間葉系幹細胞由来細胞外小胞による脊髄損傷治療の最適化

  Project Year :

  2024.09

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  2025.03

   

  Authorship： Principal investigator

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

  基盤研究(C)

  Project Year :

  2024.04

  -

  2027.03

   

  岡 真一, 鵜飼 亮, 横山 貴裕, 中崎 公仁

• 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

  基盤研究(C)

  Project Year :

  2024.04

  -

  2027.03

   

  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

• 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

  基盤研究(C)

  Project Year :

  2024.04

  -

  2027.03

   

  長濱 宏史, 佐々木 祐典, 本望 修, 中崎 公仁

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Presentations 【 display / non-display 】

Presentations 【 display / non-display 】

• Systemic administration of mesenchymal stem cells inhibits reperfusion injury following intravenous rt-PA therapy for transient middle cerebral artery occlusion in rats

   [Invited]

  日本脳卒中学会総会 2016 

• 米国神経外傷学会 (Neurotrauma) Plenary session 招待講演

   [Invited]