Stroke Increases Neural Stem Cells and Angiogenesis in the Neurogenic Niche of the Adult Mouse

Abstract

The unique cellular and vascular architecture of the adult ventricular-subventricular zone (V/SVZ) neurogenic niche plays an important role in regulating neural stem cell function. However, the in vivo identification of neural stem cells and their relationship to blood vessels within this niche in response to stroke remain largely unknown. Using whole-mount preparation of the lateral ventricle wall, we examined the architecture of neural stem cells and blood vessels in the V/SVZ of adult mouse over the course of 3 months after onset of focal cerebral ischemia. Stroke substantially increased the number of glial fibrillary acidic protein (GFAP) positive neural stem cells that are in contact with the cerebrospinal fluid (CSF) via their apical processes at the center of pinwheel structures formed by ependymal cells residing in the lateral ventricle. Long basal processes of these cells extended to blood vessels beneath the ependymal layer. Moreover, stroke increased V/SVZ endothelial cell proliferation from 2% in non-ischemic mice to 12 and 15% at 7 and 14 days after stroke, respectively. Vascular volume in the V/SVZ was augmented from 3% of the total volume prior to stroke to 6% at 90 days after stroke. Stroke-increased angiogenesis was closely associated with neuroblasts that expanded to nearly encompass the entire lateral ventricular wall in the V/SVZ. These data indicate that stroke induces long-term alterations of the neural stem cell and vascular architecture of the adult V/SVZ neurogenic niche. These post-stroke structural changes may provide insight into neural stem cell mediation of stroke-induced neurogenesis through the interaction of neural stem cells with proteins in the CSF and their sub-ependymal neurovascular interaction.

Exosomes in stroke pathogenesis and therapy

“…In addition to cerebral endothelial cells, circulating endothelial progenitor cells are also involved in the generation of new blood vessels (26). Stroke-induced angiogenesis not only occurs in the periinfarct regions, but also in the ventricular/subventricular zone (V/SVZ) of the lateral ventricles, a neurogenic region (27). At early stages of recovery, angiogenic vessels are permeable, but new vessels become less leaky and functional when they mature (23,28).…”

“…V/SVZ niche, neural stem cell proliferation induced by stroke is anatomically associated with activated cerebral endothelial cells (27). Newly generated neuroblasts in the V/SVZ migrate to periinfarct regions along cerebral blood vessels (31,(39)(40)(41)(42)(43).…”

Function of neural stem cells in ischemic brain repair processes

“…In the V/SVZ niche, stroke robustly increases neural stem cells and new blood vessels, while neural stem cells directly contact blood vessels in the SVZ. 48 Co-culture of cerebral endothelial cells harvested from ischemic brain with non-ischemic V/SVZ neural progenitor cells increases progenitor cell proliferation and neuronal differentiation, whereas culture of ischemic neural progenitor cells with non-ischemic cerebral endothelial cells promotes in vitro angiogenesis as measured by a capillary tube formation assay. 111 As a further reflection of vascular and V/SVZ neural progenitor and neuroblast interaction, stroke-increased neuroblasts in the V/SVZ migrate along cerebral blood vessels to ischemic boundary regions.…”

“…Proliferating neural stem cells in the V/SVZ are observed even 30 days after ischemia. 48 Together, these stroke studies along with clonal analysis data from non-stroke rodents suggest that in response to ischemic insult, quiescent adult neural stem cells in the V/SVZ can be activated and recruited to an active pool to increase the neurogenic process.…”

“…58 Studies on adult rodent ischemic brain show that stroke activates neural stem cells to proliferate in the V/SVZ. 14,48 For example, depletion of actively dividing neural progenitor cells, but not quiescent neural stem cells, in the V/SVZ using an antimitotic agent (cytosineb-D-arabiofuranoside, Ara-C) leads to a rapid repopulation of neural progenitor cells and neuroblasts in the ischemic V/SVZ after termination of the Ara-C treatment, suggesting that neural stem cells regenerate ablated neural progenitor cells.…”