Mechanisms and Functional Significance of Stroke-Induced Neurogenesis

Abstract

Stroke affects one in every six people worldwide, and is the leading cause of adult disability. After stroke, some limited spontaneous recovery occurs, the mechanisms of which remain largely unknown. Multiple, parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. For years, clinical studies have tried to use exogenous cell therapy as a means of brain repair, with varying success. Since the rediscovery of adult neurogenesis and the identification of adult neural stem cells in the late nineties, one promising field of investigation is focused upon triggering and stimulating this self-repair system to replace the neurons lost following brain injury. For instance, it is has been demonstrated that the adult brain has the capacity to produce large numbers of new neurons in response to stroke. The purpose of this review is to provide an updated overview of stroke-induced adult neurogenesis, from a cellular and molecular perspective, to its impact on brain repair and functional recovery.

Keywords: neurogenesis; niches; stem cells; stroke; therapy.

Figure 1

Cellular origin of stroke-induced neurogenesis. (A) In the healthy brain, adult neural stem cells are found to proliferate in the SGZ of the DG, in the SVZ along the lateral ventricle (green) and the HVZ and HPZ along the third ventricle (red). (B) In the ischemic brain, proliferating adult neural stem cells are found along the third ventricle, the fourth ventricle (4V) and the CVOs (SFO, OVLT, Subcommissural organ, area postrema) (Red) as well as directly in the ischemic parenchyma (orange), besides classical neurogenic niches (Lin and Iacovitti, 2015). HVZ, hypothalamic ventricular zone; HPZ, hypothalamic proliferating zone; CVOs, Circumventricular organs; SFO, subfornical organ; OVLT, organum vasculosum of the lamina terminalis.

Figure 2

Regulation of stroke-induced neurogenesis in a standard neurogenic niche. In the healthy brain, adult neural stem cells (Dark green) present in neurogenic niches contact blood vessels, proliferate and give rise to neuroblasts migrating from the SVZ to the olfactory bulb or from an other neurogenic niche to the local parenchyma (upper panel). Following stroke, reactive astrocytes, activated microglia, and endothelial cells release chemokines and growth factors able to reach neurogenic niches, increasing NSCs proliferation and attracting migrating neuroblasts to the ischemic area. Moreover, reactive astrocytes, NG2+ cells and pericytes are able to dedifferentiate into neurons inside the damaged parenchyma (lower panel; Hermann et al., ; Sawada et al., 2014).