Endothelial Cells Support Survival, Proliferation, and Neuronal Differentiation of Transplanted Adult Ischemia-Induced Neural Stem/Progenitor Cells After Cerebral Infarction

Abstract

Transplantation of neural stem cells (NSCs) has been proposed as a therapy for a range of neurological disorders. To realize the potential of this approach, it is essential to control survival, proliferation, migration, and differentiation of NSCs after transplantation. NSCs are regulated in vivo, at least in part, by their specialized microenvironment or ''niche.'' In the adult central nervous system, neurogenic regions, such as the subventricular and subgranular zones, include NSCs residing in a vascular niche with endothelial cells. Although there is accumulating evidence that endothelial cells promote proliferation of NSCs in vitro, there is no description of their impact on transplanted NSCs. In this study, we grafted cortex-derived stroke-induced neural stem/progenitor cells, obtained from adult mice, onto poststroke cortex in the presence or absence of endothelial cells, and compared survival, proliferation, and neuronal differentiation of the neural precursors in vivo. Cotransplantation of endothelial cells and neural stem/progenitor cells increased survival and proliferation of ischemia-induced neural stem/ progenitor cells and also accelerated neuronal differentiation compared with transplantation of neural precursors alone. These data indicate that reconstitution of elements in the vascular niche enhances transplantation of adult neural progenitor cells.

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

“…However, accumulating evidence indicates that NSPCs are present in many parts of the adult brain, including the cortex [8][9][10], subcortical white matter [11], and spinal cord [12][13][14]; that is, outside conventional neurogenic zones, including SVZ and SGZ. Recently, we also found that NSPCs developed in the poststroke area of the cortex in the adult murine brain (ischemia-induced NSPCs) [8], and that ECs promoted the proliferation of these NSPCs, thereby enhancing neurogenesis after ischemia [15]. These observations suggest that augmentation of ECs (e.g., proliferation of ECs [angiogenesis]) can promote neurogenesis by enhancing the proliferation of endogenous ischemia-induced NSPCs.…”

“…In brief, the left MCA was isolated, electrocauterized, and disconnected just distal to its crossing of the olfactory tract (distal M1 portion) under halothane inhalation. The infarct area in mice of this background has been shown to be highly reproducible and limited to the ipsilateral cerebral cortex [8,15,33,34].…”

“…Permanent focal cerebral ischemia was produced by ligation and disconnection of the distal portion of the left middle cerebral artery (MCA) [8,15,33,34]. In brief, the left MCA was isolated, electrocauterized, and disconnected just distal to its crossing of the olfactory tract (distal M1 portion) under halothane inhalation.…”

“…Immunohistochemistry was performed as described previously [8,15]. Detailed conditions are in the Supporting Information Materials and Methods.…”

“…Transplantation of ECs was performed as described previously [15]. Detailed protocol is in the Materials and Methods Section of Supporting Information.…”