title: Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes angiogenesis and neurogenesis after cerebral ischemia in rats.
abstract: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is a potential therapy for cerebral ischemia. Although BMSCs-induced angiogenesis is considered important for neurological functional recovery, the neurorestorative mechanisms are not fully understood. We examined whether BMSCs-induced angiogenesis enhances cerebral tissue perfusion and creates a suitable microenvironment within the ischemic brain, which in turn accelerates endogenous neurogenesis and leads to improved functional recovery. Adult female rats subjected to 2 h middle cerebral artery occlusion (MCAO) were transplanted with a subpopulation of human BMSCs from male donors (Flk-1+ hBMSCs) or saline into the ipsilateral brain parenchymal at 3 days after MCAO. Flk-1+ hBMSCs-treated rats exhibited significant behavioral recovery, beginning at 2 weeks after cerebral ischemia compared with controls. Moreover, rats treated with Flk-1+ hBMSCs showed increased glucose metabolic activity and reduced infarct volume. Flk-1+ hBMSCs treatment significantly increased the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, promoted angiogenesis, and facilitated cerebral blood flow in the ischemic boundary zone. Further, Flk-1+ hBMSCs treatment enhanced proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone and subgranular zone of the hippocampus. Finally, more NSPCs migrated toward the ischemic lesion and differentiated to mature neurons or glial cells with less apoptosis in Flk-1+ hBMSCs-treated rats. These data indicate that angiogenesis induced by Flk-1+ hBMSCs promotes endogenous neurogenesis, which may cause functional recovery after cerebral ischemia.
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xinjie
authors.initials: X
authors.lastname: Bao
authors.forename: Ming
authors.initials: M
authors.lastname: Feng
authors.forename: Junji
authors.initials: J
authors.lastname: Wei
authors.forename: Qin
authors.initials: Q
authors.lastname: Han
authors.forename: Hao
authors.initials: H
authors.lastname: Zhao
authors.forename: Guilin
authors.initials: G
authors.lastname: Li
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhu
authors.forename: Haiqun
authors.initials: H
authors.lastname: Xing
authors.forename: Yihua
authors.initials: Y
authors.lastname: An
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.forename: Robert Chunhua
authors.initials: RC
authors.lastname: Zhao
authors.forename: Renzhi
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D040301:Vascular Endothelial Growth Factor Receptor-2; D005947:Glucose