Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and <i>ex vivo</i> HGF Gene Transfer with HSV-1 Vector

Journal of Cerebral Blood Flow and Metabolism - Tập 26 Số 9 - Trang 1176-1188 - 2006
Ming-Zhu Zhao1,2, Naosuke Nonoguchi1, Naokado Ikeda1, Takuji Watanabe1, Daisuke Furutama3, Daisuke Miyazawa4, Hiroshi Funakoshi4, Yoshinaga Kajimoto1, Toshikazu Nakamura4, Mari Dezawa5, Masaaki Shibata6, Yoshinori Otsuki6, Robert S. Coffin7, Weidong Liu2, Toshihiko Kuroiwa1, Shin-Ichi Miyatake1
1Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, Japan
2Department of Neurosurgery, Pu Nan Hospital, Shanghai, People's Republic of China
3First Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
4Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
5Department of Anatomy and Neurobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan
6Department of Anatomy and Biology, Osaka Medical College, Takatsuki, Osaka, Japan
7Department of Molecular Pathology in Windeyer Institute of Medical Sciences of University College, London, UK

Tóm tắt

Occlusive cerebrovascular disease leads to brain ischemia that causes neurological deficits. Here we introduce a new strategy combining mesenchymal stromal cells (MSCs) and ex vivo hepatocyte growth factor (HGF) gene transferring with a multimutated herpes simplex virus type-1 vector in a rat transient middle cerebral artery occlusion (MCAO) model. Gene-transferred MSCs were intracerebrally transplanted into the rats' ischemic brains at 2h (superacute) or 24 h (acute) after MCAO. Behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphate-buffered saline (PBS)-treated and MSCs-only-treated group. The significant difference of infarction areas on day 3 was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase.

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Tài liệu tham khảo

10.1073/pnas.95.7.3908

10.1161/01.STR.17.6.1304

10.1016/S1471-4914(01)02016-0

10.1016/S0028-3908(00)00006-X

10.1161/01.STR.32.4.1005

10.1002/jnr.10334

10.1046/j.1440-1789.2002.00450.x

10.1016/S1474-4422(02)00040-6

10.1097/00001756-200009110-00035

10.1099/0022-1317-79-12-3019

10.1016/S0301-472X(00)00134-X

10.2174/1566523024605645

10.1212/WNL.59.4.486

10.1089/152581601750098372

Friedenstein AJ, 1978, Exp Hematol, 6, 440

10.1038/sj.gt.3301498

10.1002/(SICI)1097-4652(199603)166:3<585::AID-JCP13>3.0.CO;2-6

10.1124/jpet.102.041772

10.1097/00001756-200207020-00023

10.1016/j.ymthe.2004.09.020

10.1016/j.ymthe.2003.10.012

10.1212/WNL.59.4.514

10.1212/WNL.56.12.1666

10.1097/00004647-200009000-00006

10.1128/JVI.75.9.4343-4356.2001

10.1161/01.STR.20.1.84

10.1093/oxfordjournals.jbchem.a021283

10.1006/bbrc.1997.7517

McIntosh K, 2000, Graft, 3, 324

10.1097/00004647-199804000-00001

10.1016/0006-291X(84)91253-1

10.1097/00007890-200106270-00006

10.1002/jgm.498

10.1128/JVI.74.12.5604-5618.2000

10.1016/0165-0270(85)90026-3

10.1002/jcb.10084

10.1038/jcbfm.1990.47

10.1212/WNL.59.4.486

Schallert T, 1997, Adv Neurol, 73, 229

10.1161/01.CIR.0000109496.82683.49

10.1016/S0169-328X(02)00168-7

10.1523/JNEUROSCI.22-15-06537.2002

10.1038/sj.gt.3301105

Tsuzuki N, 2000, Acta Neurochir Suppl, 76, 311

10.1097/01.WCB.0000136525.75839.41

10.1073/pnas.83.23.9231

10.1002/1097-4547(20000815)61:4<364::AID-JNR2>3.0.CO;2-C

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Journal of Cerebral Blood Flow and Metabolism

Tập 26 Số 9

1176-1188

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