Subventricular zone cytogenesis provides trophic support for neural repair

Abstract

AbstractStroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here we characterize the identity of cells arising from the SVZ after stroke and provide insight into their function by uncovering a mechanism through which they facilitate neural repair and functional recovery. Using genetic lineage tracing, we show that SVZ-derived cells that migrate towards stroke- induced cortical lesions in mice are predominantly undifferentiated precursors, suggesting that the main function of post-injury cytogenesis is not cell replacement. We find that SVZ-derived cells are a unique cellular source of trophic factors that instruct neural repair. Chemogenetic ablation of neural precursor cells or conditional knockout of VEGF in the adult neural stem cell lineage impairs neuronal and vascular reparative responses and worsens functional recovery after stroke. In addition, normal aging markedly diminishes the cytogenic response to stroke, resulting in worse functional recovery. Therapeutic replacement of VEGF in peri-infarct cortex is sufficient to induce neural repair and functional recovery in mice with arrested cytogenesis. These findings indicate that the SVZ cytogenic response following brain injury is a source of trophic support that drives neural repair and recovery.