Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats.
Mesenchymal stem cells (MSCs) have been successfully used for the treatment of experimental stroke. However, the neurorestorative mechanisms by which MSCs improve neurological functional recovery are not fully understood. Endogenous cell proliferation in the subventricular zone (SVZ) after stroke is well known, but most of newly formed cells underwent apoptosis. In the present study, we tested the hypothesis that neurotrophic factors secreted by human bone marrow-derived MSCs (hBMSCs) promote endogenous neurogenesis, reduce apoptosis, and improve functional recovery. Adult rats subjected to 2-h middle cerebral artery occlusion (MCAO) were transplanted with hBMSCs or saline into the ipsilateral brain parenchyma at 3days after ischemia. There was a significant recovery of behavior in the hBMSCs-treated rats beginning at 14days after MCAO compared with the control animals. Higher levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and vascular endothelial growth factor (VEGF) were detected in the hBMSCs-treated rat brain than the control. Human BMSCs treatment also enhanced endogenous cell proliferation both in the SVZ and in the subgranular zone (SGZ) of the hippocampus. In addition, more neuronal progenitor cells migrated from the SVZ to the ischemic boundary zone (IBZ) and differentiated into mature neurons with less apoptosis in rats treated with hBMSCs. Overall, these data suggest an essential role for hBMSCs in promoting endogenous neurogenesis, protecting newly formed cells, and improving functional recovery after ischemia in rats.
Bao
Xinjie
X
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China.
Wei
Junji
J
Feng
Ming
M
Lu
Shan
S
Li
Guilin
G
Dou
Wanchen
W
Ma
Wenbin
W
Ma
Sihai
S
An
Yihua
Y
Qin
Chuan
C
Zhao
Robert Chunhua
RC
Wang
Renzhi
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal; D001854:Bone Marrow Cells / Q000502:physiology*; D020520:Brain Infarction / Q000601:surgery; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000601:surgery*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D020127:Recovery of Function / Q000502:physiology*; D012720:Severity of Illness Index; D013997:Time Factors; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D020933:Neurotrophin 3; D042442:Vascular Endothelial Growth Factors; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine