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Author(s): Yasuhara T (Yasuhara, Takao); Matsukawa N (Matsukawa, Noriyuki); Hara K (Hara, Koichi); Maki M (Maki, Mina); Ali MM (Ali, Mohammed M.); Yu SJ (Yu, Seong Jin); Bae E (Bae, Eunkyung); Yu GL (Yu, Guolong); Xu L (Xu, Lin); McGrogan M (McGrogan, Michael); Bankiewicz K (Bankiewicz, Krys); Case C (Case, Casey); Borlongan CV (Borlongan, Cesar V.)
Title: Notch-Induced Rat and Human Bone Marrow Stromal Cell Grafts Reduce Ischemic Cell Loss and Ameliorate Behavioral Deficits in Chronic Stroke Animals
Source: STEM CELLS AND DEVELOPMENT 18 (10): 1501-1513
Date: 2009 DEC
Document Type: Journal : Article
DOI: 10.1089/scd.2009.0011
Language: English
Comment:
Address: Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA.
SanBio Inc, Mountain View, CA USA. Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. Reprint: Borlongan, CV, Univ S Florida, Dept Neurosurg, Coll Med, Tampa, FL
33612 USA. E-mail: cborlong@health.usf.edu
Author Keywords:
KeyWords Plus: FOCAL CEREBRAL-ISCHEMIA; NEURAL STEM-CELLS; CORD BLOOD-CELLS;
PARKINSONS-DISEASE; IMMUNOLOGICAL RESPONSE; FUNCTIONAL RECOVERY; ARTERY
OCCLUSION; NEURONAL CELLS; ADULT RATS; TRANSPLANTATION
Abstract: Gene transfection with Notch 1 intracellular domain and subsequent growth factor treatment stimulate neuron-like differentiation of bone marrow stromal cells (BMSCs). Here, we examined the potential of transplanting Notch-induced BMSCs to exert therapeutic effects in a rat model of chronic ischemic stroke. In experiment 1, Notch-induced rat BMSCs were intrastriatally transplanted in rats at 1 month after being subjected to transient occlusion of middle cerebral artery (MCAo). Compared to post-stroke/pretransplantation level, significant improvements in locomotor and neurological function were detected in stroke rats that received 100 k and 200 k BMSCs, but not in those that received 40 k BMSCs. Histological results revealed 9%-15% graft survival, which dose-dependently correlated with behavioral recovery. At 5 weeks post-transplantation, some grafted BMSCs were positive for the glial marker GFAP (about 5%), but only a few cells (2-5 cells per brain) were positive for the neuronal marker NeuN. However, at 12 weeks post-transplantation, where the number of GFAP-positive BMSCs was maintained (5%), there was a dramatic increase in NeuN-positive BMSCs (23%). In experiment 2, Notch-induced human BMSCs were intrastriatally transplanted in rats at 1 month following the same MCAo model. Improvements in both locomotor and neurological function were observed from day 7 to day 28 post-transplantation, with the high dose (180 k) displaying significantly better behavioral recovery than the low dose (90 k) or vehicle. There were no observable adverse behavioral effects during this study period that also involved chronic immunosuppression of all animals. Histological analyses revealed a modest 5%-7% graft survival, with few (<1%) cells expressing an intermediate MAP2 neuronal marker, but not glial or oligodendroglial markers. In addition, striatal peri-infarct cell loss was significantly reduced in transplanted stroke animals compared to vehicle-treated stroke animals. The present study demonstrates the potential of Notch-induced BMSC cell therapy for patients presenting with fixed ischemic stroke.
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