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Misc - HONMOU Osamu

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宝金清博, 本望修

医学のあゆみ ( 医歯薬出版(株) ) 212 ( 6 ) 569 - 574 2005.02

Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model

K Kurozumi, K Nakamura, T Tamiya, Y Kawano, K Ishii, M Kobune, S Hirai, H Uchida, K Sasaki, Y Ito, K Kato, O Honmou, K Houkin, Date, I, H Hamada

MOLECULAR THERAPY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 11 ( 1 ) 96 - 104 2005.01

Mesenchymal stem cells (MSC) were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we previously transfected the telomerized human MSC with the BDNF gene using a fiber-mutant adenovirus vector and reported that such treatment contributed to improved ischemic recovery in a rat transient middle cerebral artery occlusion (MCAO) model. In the present study, we investigated whether other cytokines in addition to BDNF, i.e., GDNF, CNTF, or NT3, might have a similar or greater effect in this model. Rats that received MSC-BDNF (P < 0.05) or MSC-GDNF (P < 0.05) showed significantly more functional recovery as demonstrated by improved behavioral test results and reduced ischemic damage on MRI than did control rats 7 and 14 days following MCAO. On the other hand, rats that received MSC-CNTF or MSC-NT3 showed neither functional recovery nor ischemic damage reduction compared to control rats. Thus, MSC transfected with the BDNF or GDNF gene resulted in improved function and reduced ischemic damage in a rat model of MCAO. These data suggest that gene-modified cell therapy may be a useful approach for the treatment of stroke.

DOI

Autologous transplantation of expanded neural precursor cells into the demyelinated monkey spinal cord

S Oka, O Honmou, Y Akiyama, M Sasaki, K Houkin, K Hashi, JD Kocsis

BRAIN RESEARCH ( ELSEVIER SCIENCE BV ) 1030 ( 1 ) 94 - 102 2004.12

The objective of this study was to establish if neural precursor cells could safely be developed from biopsy of the subventricular zone (SVZ) in the non-human primate (marmoset), and to determine their myelinating potential after autologous transplantation into a demyelinated lesion. Small amounts of tissue were safely collected from the subventricular-subependymal zone of the adult primate brain under ultrasonography without any neurological deficit. Neural precursor cells were isolated and expanded in the presence of mitogen in vitro. The dorsal columns of the adult marmoset spinal cord were demyelinated by X-irradiation and intraspinal injections of ethidium bromide in the center of the radiation field. Cell suspensions of the neural precursors were microinjected through a micropipette into the demyelinated lesion site in the spinal cord. Lesions were histologically examined 3 weeks after transplantation. Light and electron microscopic examination of plastic embedded sections revealed a significant number of myelinating profiles in the transplantation zone; no myelination was observed in control lesions. The myelinated axons had predominantly peripheral patterns of myelination. These results demonstrate that autologous transplantation of neural precursor cells in the adult nonhuman primate can remyelinate demyelinated central nervous system (CNS) axons, thus suggesting the potential utility of such an approach in demyelinating lesions in humans. (C) 2004 Elsevier B.V. All rights reserved.

DOI

Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model

K Nakamura, Y Ito, Y Kawano, K Kurozumi, M Kobune, H Tsuda, A Bizen, O Honmou, Y Niitsu, H Hamada

GENE THERAPY ( NATURE PUBLISHING GROUP ) 11 ( 14 ) 1155 - 1164 2004.07

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 cell 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 caused significant inhibition of 9L tumor growth and increased the survival of 9L glioma-bearing rats. Gene-modification of MSCs by infection with an adenoviral vector encoding human interleukin-2 (IL-2) 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 brain tumor.

DOI

脳神経外科における産学官連携

本望修, 宝金清博

Neurological Surgery ( (株)医学書院 ) 32 ( 6 ) 571 - 577 2004.06

A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats

S Iihoshi, O Honmou, K Houkin, K Hashi, JD Kocsis

BRAIN RESEARCH ( ELSEVIER SCIENCE BV ) 1007 ( 1-2 ) 1 - 9 2004.05

The primary objective of this study was to test the hypothesis that intravenous administration of autologous bone marrow cells could improve functional recovery after middle cerebral artery occlusion (MCAO) for 45 min in the rat and to determine specific time windows for efficacy. Mononuclear cells from autologous bone marrow were transfected with the LacZ reporter gene, and injected intravenously into rats at 3-72 h after induction of MCAO. Histological analysis of the ischemic lesion at 14 days after transplantation revealed reduced ischemic lesion volume. Lesion volume was 250 +/- 45 mm(3) (n = 6) after MCAO without cell transplantation. Lesions were minimally detected by absence of 2,3,5-triphenyltetrazolium chloride (TTC) staining when bone marrow cells were infused 3 h after lesion induction. Lesions were clearly detected beginning with the 6-h postlesion group and became progressively larger at 12, 24 and 72 h (80 +/- 25, 140 +/- 18, and 180 +/- 22 mm(3), respectively; n=6 for each group). Transplanted LacZ(+) bone marrow cells accumulated extensively in and around the ischemic lesions, and immunohistochemistry suggests some neuronal and glial lineage differentiation. Behavioral testing (Morris water maze and Treadmill stress test) indicated greater functional recovery in the treated group. These findings suggest that early intervention with intravenous administration of autologous mononuclear cells from bone marrow can reduce lesion size in the MCAO model in the rat, and improve functional outcome. (C) 2004 Elsevier B.V. All rights reserved.

DOI

BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model (vol 9, pg 189, 2004)

K Kurozumi, K Nakamura, T Tamiya, Y Kawano, M Kobune, S Hirai, H Uchida, K Sasaki, Y Ito, K Kato, O Honmou, K Houkin, Date, I, H Hamada

MOLECULAR THERAPY 9 ( 5 ) 766 - 766 2004.05

Other

DOI

Cytokine gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model

K Kurozumi, K Nakamura, T Ichikawa, Y Ono, T Tamiya, Y Ito, O Honmou, K Houkin, H Hamada, Date, I

MOLECULAR THERAPY 9 S20 - S20 2004.05

Research paper, summary (international conference)

BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model

K Kurozumi, K Nakamura, T Tamiya, Y Kawano, M Kobune, S Hirai, H Uchida, K Sasaki, Y Ito, K Kato, O Honmou, K Houkin, Date, I, H Hamada

MOLECULAR THERAPY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 9 ( 2 ) 189 - 197 2004.02

Examination of the clinical therapeutic efficacy of using bone marrow stromal cells, including mesenchymal stem cells (MSC), has recently been the focus of much investigation. MSC were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we transfected telomerized human MSC with the BDNF gene using a fiber-mutant F/RGD adenovirus vector and investigated whether these cells contributed to improved functional recovery in a rat transient middle cerebral artery occlusion (MCAO) model. BDNF production by MSC-BDNF cells was 23-fold greater than that seen in uninfected MSC. Rats that received MSC-BDNF showed significantly more functional recovery than did control rats following MCAO. Specifically, MRI analysis revealed that the rats in the MSC-BDNF group exhibited more significant recovery from ischemia after 7 and 14 days. The number of TUNEL-positive cells in the ischemic boundary zone was significantly smaller in animals treated with MSC-BDNF compared to animals in the control group. These data suggest that MSC transfected with the BDNF gene may be useful in the treatment of cerebral ischemia and may represent a new strategy for the treatment of stroke.

DOI

[Consequence of intellectual property and consortium project in neurosurgery]

Osamu Honmou, Kiyohiro Houkin

No Shinkei Geka 32 ( 6 ) 571 - 7 2004 [Domestic journal]

PubMed

Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord

M Inoue, O Honmou, S Oka, K Houkin, K Hashi, JD Kocsis

GLIA ( WILEY-LISS ) 44 ( 2 ) 111 - 118 2003.11

The remyelinating potential of autologous bone marrow cells was studied after direct injection and following intravenous injection into rats with a demyelinated lesion in the spinal cord. Both focal and intravenous injections of acutely isolated mononuclear bone marrow cell fractions resulted in varying degrees of remyelination. Suspensions of bone marrow cells collected from the same rat were delivered at varied concentrations (10(2) to 10(5) for direct injection and 10(4) to 10(7) for i.v. injections). The lesions were examined histologically 3 weeks after transplantation. Light microscopic examination revealed remyelination in the dorsal funiculus with both injection protocols, but the extent of remyelination was proportional to the number of injected cells. To attain the same relative density of remyelination achieved by direct injection, intravenous administration of cells required delivery of substantially more cells (two orders of magnitude). However, the availability of autologous bone marrow cells in large number and the potential for systemically delivering cells to target lesion areas without neurosurgical intervention suggest the potential utility of intravenous cell delivery as a prospective therapeutic approach in demyelinating disease. (C) 2003 Wiley-Liss, Inc.

DOI

Telomerized human multipotent mesenchymal cells can differentiate into hematopoietic and cobblestone area-supporting cells

M Kobune, Y Kawano, Y Ito, H Chiba, K Nakamura, H Tsuda, K Sasaki, H Dehari, H Uchida, O Honmou, S Takahashi, A Bizen, R Takimoto, T Matsunaga, J Kato, K Kato, K Houkin, Y Niitsu, H Hamada

EXPERIMENTAL HEMATOLOGY ( ELSEVIER SCIENCE INC ) 31 ( 8 ) 715 - 722 2003.08

Objective. To compare the hematopoietic support provided by telomerized human mesenchymal stem cells (MSCs) and telomerized MSC-derived stromal cells. Methods. We transfected the human telomerase catalytic subunit (hTERT) gene into primary MSCs to establish hTERT-transduced MSCs (hTERT-MSCs). Stromal induction of hTERT-MSCs was performed by replacing the culture medium with Dexter-type culture medium. Hematopoietic support was examined by coculture with cord blood CD34(+) cells. Results. The hTERT-MSCs were morphologically identical with the primary MSCs and expressed surface antigens including CD105, CD73, and CD166. hTERT-MSCs showed a similar doubling time as primary MSCs and continued to proliferate to over 80 population doublings (PD), although the primary MSCs underwent crisis in vitro at 16 PD. The osteogenic, chondrogenic, adipogenic, neurogenic, and stromal differentiation potential of hTERT-MSCs were maintained up to at least 40 PD. The degree of expansion of CD34+ cells and total number of colony-forming units in culture (CFU-C) upon 12-day coculture with the hTERT-MSC-derived stromal cells were nearly the same as those upon 12-day coculture with hTERT-MSCs (CD34, 33.0-fold +/- 2.8-fold vs 36.1-fold +/- 1.7-fold of the initial cell number; CFUs, 344.4-fold +/- 62.5-fold vs 239.3-fold +/- 87.0-fold; CFU-mix, 368.4-fold +/- 113.7-fold vs 341.3-fold +/- 234.3-fold). However, on day 18 of coculture, the number of cobblestone areas (CA) observed beneath the stromal cells was 15 times higher than that beneath hTERT-MSCs (CA, 146.9 +/- 54.6 vs 9.4 +/- 8.1, p < 0.01). Conclusion. Stromal induction of hTERT-MSCs exclusively enhanced the support of CA formation provided by hTERT-MSCs. Our human hTERT-MSCs will be useful for elucidating the mechanism of the formation of CAs. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI

Differential gene expression screening between parental and highly metastatic pancreatic cancer variants using a DNA microarray

H Tanaka, F Hata, H Nishimori, O Honmou, T Yasoshima, H Nomura, K Ohno, Hirai, I, K Kamiguchi, H Isomura, Y Hirohashi, R Denno, N Sato, K Hirata

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 22 ( 2 ) 307 - 313 2003.06

迷走神経刺激療法が著効したLennox-Gastaut症候群の1女児例

若井周治, 二階堂弘輝, 堤裕幸, 本望修, 宝金清博, 川本芳誉

日本小児科学会雑誌 ( (公社)日本小児科学会 ) 107 ( 5 ) 849 - 849 2003.05

Awake surgeryによる運動性言語領野の同定の試み

本望修, 鰐淵昌彦, 南田善弘, 田邊純嘉, 宝金清博

臨床神経生理学 ( (一社)日本臨床神経生理学会 ) 31 ( 2 ) 216 - 216 2003.04

神経幹細胞移植

Clin Ｎeurosci 21 542 - 542 2003

細胞移植療法による神経再生戦略

最新医学 58 677 - 684 2003

神経再生医療の基礎知識

脊椎脊髄ジャーナル 16 101 - 105 2003

Transplantation of mesenchymal stem cells derived from the bone marrow into the demyelinated spinal cord

A Bizen, O Honmou, M Inoue, S Iihoshi, K Houkin, K Hashi

MOLECULAR MECHANISMS AND EPOCHAL THERAPEUTICS OF ISCHEMIC STROKE AND DEMENTIA 1252 471 - 475 2003

DOI

脳卒中に対する再生医療の展望

最新医学 58 899 - 903 2003

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