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Published on: October 1, 2020
Vasculogenesis in experimental stroke after human cerebral endothelial cell transplantation
Hiroto Ishikawa1, Naoki Tajiri, Kazutaka Shinozuka
1From the Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL (H.I., N.T., K.S., J.V., Y.K., C.V.B.); Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya, Japan (H.I., O.M.); Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea (H.J.L.); Department of Stem Cell Biology and Histology and Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japan (M.D.); and Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada (S.U.K.).
Background And Purpose:
Despite the reported functional recovery in transplanted stroke models and patients, the mechanism of action underlying stem cell therapy remains not well understood. Here, we examined the role of stem cell-mediated vascular repair in stroke.
Methods:
Adult rats were exposed to transient occlusion of the middle cerebral artery and 3 hours later randomly stereotaxically transplantated with 100K, 200K, or 400K human cerebral endothelial cell 6 viable cells or vehicle. Animals underwent neurological examination and motor test up to day 7 after transplantation then euthanized for immunostaining against neuronal, vascular, and specific human antigens. A parallel in vitro study cocultured rat primary neuronal cells with human cerebral endothelial cell 6 under oxygen-glucose deprivation and treated with vascular endothelial growth factor (VEGF) and anti-VEGF.
Results:
Stroke animals that received vehicle infusion displayed typical occlusion of the middle cerebral artery-induced behavioral impairments that were dose-dependently reduced in transplanted stroke animals at days 3 and 7 after transplantation and accompanied by increased expression of host neuronal and vascular markers adjacent to the transplanted cells. Some transplanted cells showed a microvascular phenotype and juxtaposed to the host vasculature. Infarct volume in transplanted stroke animals was significantly smaller than vehicle-infused stroke animals. Moreover, rat neurons cocultured with human cerebral endothelial cell 6 or treated with VEGF exhibited significantly less oxygen-glucose deprivation-induced cell death that was blocked by anti-VEGF treatment.
Conclusions:
We found attenuation of behavioral and histological deficits coupled with robust vasculogenesis and neurogenesis in endothelial cell-transplanted stroke animals, suggesting that targeting vascular repair sets in motion a regenerative process in experimental stroke possibly via the VEGF pathway.
