A neurovascular niche for neurogenesis and functional recovery after stroke.

摘要

Stroke causes a localized process of ischemic cell death in the brain, but it also triggers a regenerative response in the tissue adjacent to this area of cell death. Stroke induces the proliferation of adult neural stem cells and the migration of immature neurons within ischemic tissue. This stem cell response generates a limited number of new neurons at the site of stroke damage, suggesting this regenerative process might be harnessed for neuronal replacement after stroke. To define the cellular environment that induces neuronal regeneration and migration, we used a model of focal cortical stroke that induces the long distance migration of newly born neuroblasts from the subventricular zone (SVZ) to peri-infarct cortex. Using mitotic and genetic labeling and chemokine/growth factor gain- and loss-of-function studies, we show that stroke induces neurogenesis from a GFAP-expressing progenitor cell in the SVZ into a unique neurovascular niche in peri-infarct cortex. Within this niche, migrating, newly born neuroblasts closely associate with the remodeling vasculature. Neurogenesis and angiogenesis are causally linked through vascular production of stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1). Further, SDF1 and Ang1 promote post-stroke neuroblast migration and behavioral recovery. We next examined the role of the endogenous erythropoietin system in normal and post-stroke neurogenesis. By generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to significantly reduced cell proliferation in the SVZ and impaired post-stroke neurogenesis. EpoR conditional knockdown leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results suggest that the classical EPOR is important for adult neurogenesis and for migration of regenerating neurons during post-injury recovery. Together, the studies in this dissertation define a novel brain environment in which neuronal progenitor and vascular interactions comprise a regenerative cellular niche.