Cellular Response of Ventricular-Subventricular Neural Progenitor/Stem Cells to Neonatal Hypoxic-Ischemic Brain Injury and Their Enhanced Neurogenesis

Abstract

Purpose: To elucidate the brain's intrinsic response to injury, we tracked the response of neural stem/progenitor cells (NSPCs) located in ventricular-subventricular zone (V-SVZ) to hypoxic-ischemic brain injury (HI). We also evaluated whether transduction of V-SVZ NSPCs with neurogenic factor NeuroDI could enhance their neurogenesis in HI. Materials and Methods: Unilateral HI was induced in ICR neonatal mice. To label proliferative V-SVZ NSPCs in response to HI, bromodeoxyuridine (BrdU) and retroviral partides encoding LacZ or NeuroD1/GFP were injected. The cellular responses of NSPCs were analyzed by immunohistochemistry. Results: Unilateral HI increased the number of BrdU(+) newly-born cells in the V-SVZ ipsilateral to the lesion while injury reduced the number of newly-born cells reaching the ipsilateral olfactory bulb, which is the programmed destination of migratory V-SVZ NSPCs in the intact brain. These newly-born cells were directed from this pathway towards the lesions. HI significantly increased the number of newly-born cells in the cortex and striatum by the altered migration of V-SVZ cells. Many of these newly-born cells differentiated into active neurons and glia. LacZ-expressing V-SW NSPCs also showed extensive migration towards the non-neurogenic regions ipsilateral to the lesion, and expressed the neuronal marker NeuN. NeuroD1(+)/GFP(+) V-SVZ NSPCs almost differentiated into neurons in the peri-infarct regions. Conclusion: HI promotes the establishment of a substantial number of new neurons in non-neurogenic regions, suggesting intrinsic repair mechanisms of the brain, by controlling the behavior of endogenous NSPCs. The activation of NeuroD1 expression may improve the therapeutic potential of endogenous NSPCs by increasing their neuronal differentiation in HI.