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 NeuroD1 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 particles 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-SVZ 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.

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

“…Postnatal neurogenesis encompasses multiple stages, including NSCs proliferation, differentiation, migration to a predetermined niche, and integration into established neural circuits 9 . Several studies 54,55 have reported a high density of proliferating cells in the subventricular zone shortly after HIBD, indicating a potential increase in subventricular neurogenesis. These exciting findings suggest that the neurogenic burst potentially acts as an adaptive response, facilitating brain recovery and enhancing neuronal replacement.…”

Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild–Moderate Neonatal Hypoxia-Ischemia Brain Injury Model

“…While other studies have showed an increase in BrdU + cells after HI [ 7 , 13 ], we could not find a significant increase in BrdU + cells in the cortex, the hippocampus, or the lateral ventricle in our mild–moderate model. Most of the data available on neurogenesis in HI animal models focused on the SVZ [ 7 , 13 , 31 ], but in the present study, we focused on broader parts of the brain. This could imply that, while neurogenesis in the SVZ is stimulated after HI, the same is not the case for other areas of the brain, or that new cells do not migrate across the injured brain at the time points analyzed.…”

“…The primary antibody (anti-Iba1, anti-NeuN) was incubated overnight at 4 °C followed by incubation of the corresponding secondary antibody for 1 h at room temperature ( Table 1 ). Iba1 is a marker used for microglia [ 16 ] and NeuN is a marker used for mature neurons [ 31 ]. For BrdU-staining, the slices were incubated with 2M HCl for 30 min at room temperature, followed by incubation with the primary antibody overnight at 4 °C and with the corresponding secondary antibody for 1 h at room temperature ( Table 1 ).…”

Research advances in the role of endogenous neurogenesis on neonatal hypoxic-ischemic brain damage

“…It was recently shown that post-neonatal HIBD can induce NSCs proliferation in neurogenesis sites, with subsequent migration of proliferating progenitor cells to a damaged brain region where they acquire the desired phenotype; furthermore, in the damaged brain region, new neurons differentiated from NSCs can integrate into functional neural loops and repair damaged nerves ( 25 ). Plane et al ( 26 ) used 5-Bromodeoxyuridine (BrdU) as a marker of proliferating cells in the Rice-Vannucci neonatal rat model of brain hypoxia-ischemia, in which they demonstrated a significant increase in BrdU-positive cells in damaged brain areas, mainly the SVZ.…”