Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery.
OBJECTIVE
To test the effect of i.v.-injected human bone marrow stromal cells (hMSC) on neurologic functional deficits after stroke in rats.


METHODS
Rats were subjected to transient middle cerebral artery occlusion and IV injected with 3 x 10(6) hMSC 1 day after stroke. Functional outcome was measured before and 1, 7, and 14 days after stroke. Mixed lymphocyte reaction and the development of cytotoxic T lymphocytes measured the immune rejection of hMSC. A monoclonal antibody specific to human cellular nuclei (mAb1281) was used to identify hMSC and to measure neural phenotype. ELISA analyzed neurotrophin levels in cerebral tissue from hMSC-treated or nontreated rats. Bromodeoxyuridine injections were used to identify newly formed cells.


RESULTS
Significant recovery of function was found in rats treated with hMSC at 14 days compared with control rats with ischemia. Few (1 to 5%) hMSC expressed proteins phenotypic of brain parenchymal cells. Brain-derived neurotrophic factor and nerve growth factor significantly increased, and apoptotic cells significantly decreased in the ischemic boundary zone; significantly more bromodeoxyuridine-reactive cells were detected in the subventricular zone of the ischemic hemisphere of rats treated with hMSC. hMSC induced proliferation of lymphocytes without the induction of cytotoxic T lymphocytes.


CONCLUSIONS
Neurologic benefit resulting from hMSC treatment of stroke in rats may derive from the increase of growth factors in the ischemic tissue, the reduction of apoptosis in the penumbral zone of the lesion, and the proliferation of endogenous cells in the subventricular zone.
Department of Neurology, Henry Ford Health Sciences Center, Detroit 48202, USA.
Y
Y
Li
J
J
Chen
X G
XG
Chen
L
L
Wang
S C
SC
Gautam
Y X
YX
Xu
M
M
Katakowski
L J
LJ
Zhang
M
M
Lu
N
N
Janakiraman
M
M
Chopp
D000818:Animals; D001522:Behavior, Animal; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000378:metabolism*; D002455:Cell Division; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006085:Graft Survival; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D009043:Motor Activity; D020932:Nerve Growth Factor / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013154:Spleen / Q000166:cytology / Q000276:immunology; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017154:Stromal Cells / Q000276:immunology / Q000637:transplantation*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D019208:Brain-Derived Neurotrophic Factor; D020932:Nerve Growth Factor