Endothelial progenitor cell transplantation improves long-term stroke outcome in mice.
OBJECTIVE
Endothelial progenitor cells (EPCs) play an important role in tissue repairing and regeneration in ischemic organs, including the brain. However, the cause of EPC migration and the function of EPCs after ischemia are unclear. In this study, we demonstrated the effects of EPCs on ischemic brain injury in a mouse model of transient middle cerebral artery occlusion (tMCAO).


METHODS
Circulating human EPCs were characterized with immunofluorescent staining and flow cytometry. EPCs (1 x 10(6)) were injected into nude mice after 1 hour of tMCAO. Histological analysis and behavioral tests were performed from day 0 to 28 days after tMCAO.


RESULTS
EPCs were detected in ischemic brain regions 24 hours after tMCAO. EPC transplantation significantly reduced ischemic infarct volume at 3 days after tMCAO compared with control animals (p < 0.05). CXCR4 was expressed in the majority of EPCs, and stromal-derived factor-1 (SDF-1) induced EPC migration, which was blocked by pretreated EPCs with AMD3100 in vitro. SDF-1 was upregulated in ischemic brain. Compared with control animals, injecting AMD3100-pretreated EPCs resulted in a larger infarct volume 3 days after tMCAO, suggesting that SDF-1-mediated signaling was involved in EPC-mediated neuroprotection. In addition, EPC transplantation reduced mouse cortex atrophy 4 weeks after tMCAO and improved neurobehavioral outcomes (p < 0.05). EPC injection potently increased angiogenesis in the peri-infarction area (p < 0.05).


CONCLUSIONS
We conclude that systemic delivery of EPCs protects the brain against ischemic injury, promotes neurovascular repair, and improves long-term neurobehavioral outcomes. Our data suggest that SDF-1-mediated signaling plays a critical role in EPC-mediated neuroprotection.
Fan
Yongfeng
Y
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Shen
Fanxia
F
Frenzel
Tim
T
Zhu
Wei
W
Ye
Jianqin
J
Liu
Jianrong
J
Chen
Yongmei
Y
Su
Hua
H
Young
William L
WL
Yang
Guo-Yuan
GY
D000704:Analysis of Variance; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001522:Behavior, Animal; D001596:Benzylamines; D039481:CD11b Antigen / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002196:Capillaries / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000637:transplantation*; D004727:Endothelium / Q000166:cytology*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology / Q000601:surgery*; D007275:Injections, Intravenous / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009043:Motor Activity / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology; D011597:Psychomotor Performance; D019718:Receptors, CXCR4 / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D018952:Antigens, CD34; D001596:Benzylamines; D039481:CD11b Antigen; C527276:CXCR4 protein, human; D015820:Cadherins; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D014841:von Willebrand Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C088327:plerixafor