Hypoxic‐ischemic brain injury activates early hippocampal stem/progenitor cells to replace vulnerable neuroblasts

Abstract

Although the phenomenon of ongoing neurogenesis in the hippocampus is well described, it remains unclear what relevance this has in terms of brain self-repair following injury. In a highly regulated developmental program, new neurons are added to the inner granular cell layer of the dentate gyrus (DG) where slowly dividing radial glial-like type 1 neural stem/progenitors (NSPs) give rise to rapidly proliferating type 2 neural progenitors which undergo selection and maturation into functional neurons. The induction of these early hippocampal progenitors after injury may represent an endogenous mechanism for brain recovery and remodeling. To determine what role early hippocampal progenitors play in remodeling following injury, we utilized a model of hypoxic-ischemic injury on young transgenic mice that express green fluorescent protein (GFP) specifically in neural progenitors. We demonstrate that this injury selectively activates programmed cell death in committed but immature neuroblasts, which is followed by proliferation of both early type 1 and later type 2 progenitors. This subsequently leads to newly generated neurons becoming stably incorporated into the DG.

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…Studies in adult rodents also suggest a limited regenerative capacity as only a few or no new neurons have been detected after HI injury. 87,88 Furthermore, studies by Miles and Kernie 89 and Nakatomi et al 87 show that HI leads to extensive loss of neurons and that only a few newly formed neurons survive up to 6 months after HI. 87,89 It is also unclear whether the newborn neuronal cells integrate into the local circuitry and become functional in the immature brain, and whether this effect is longterm.…”

“…87,88 Furthermore, studies by Miles and Kernie 89 and Nakatomi et al 87 show that HI leads to extensive loss of neurons and that only a few newly formed neurons survive up to 6 months after HI. 87,89 It is also unclear whether the newborn neuronal cells integrate into the local circuitry and become functional in the immature brain, and whether this effect is longterm. It has been described in studies using adult rodents that newborn neuronal cells show attenuated electrophysiological properties, such as field excitatory postsynaptic potentials (fEPSPs), which means that stimulation of a presynaptic terminal, e.g., the Schaffer collaterals, evokes a decreased postsynaptic response in the regenerated hippocampus.…”

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

“…Using a neural progenitorspecific, nestin-GFP-expressing transgenic mouse, these cells have been defined as types 1, 2a, 2b and 3b. 3,4,[18][19][20][21] The early neural progenitors, type 1 and 2a cells, lack committed neuronal markers and express nestin, a primitive neuroepithelial marker. In contrast, nestin expression is downregulated in late, committed neuronal progenitors or type 2b and type 3b cells; they begin to express markers of developing young neurons such as microtubule protein doublecortin (DCX) and polysialyted neural cell adhesion molecule (PS-NCAM).…”

“…In contrast, nestin expression is downregulated in late, committed neuronal progenitors or type 2b and type 3b cells; they begin to express markers of developing young neurons such as microtubule protein doublecortin (DCX) and polysialyted neural cell adhesion molecule (PS-NCAM). [20][21][22] Normally quiescent astrocyte-like type 1 cells express nestin and contain a radial glial fibrillary acidic protein (GFAP)-expressing process and are believed to represent selfrenewing stem-like cells. 23 Type 2 cells, which arise from asymmetric division of type 1 cells, represent fully committed neuroblasts.…”

Compensatory Neurogenesis in the Injured Adult Brain

“…Newly generated neurons in the dentate gyrus integrate into the existing hippocampal circuitry following TBI, potentially resulting in cognitive recovery (Sun, et al, 2005). Transgenic approaches have demonstrated that following TBI, the nestin-expressing progenitor cells are first activated by injury, whereas the later Dcx-expressing committed neuroblasts appear to be eliminated (Miles, et al, 2008, Yu, et al, 2008. Later, the Dcx-expressing cells within the dentate gyrus reemerge and are likely contributors to stable neurogenesis (Yu, et al, 2008).…”