Induction of Nanog in neural progenitor cells for adaptive regeneration of ischemic brain

Stroke: Regulatory protein key to neuronal regeneration The NANOG regulatory protein promotes neuronal regeneration by prompting the self-renewal of progenitor cells following a stroke due to blood vessel blockage (ischemic stroke). NANOG is involved in cellular plasticity and reprogramming, including the maintenance of pluripotent stem cells. Gyung-Ah Jung at the Catholic University of Korea in Seoul, South Korea, and co-workers have demonstrated that NANOG is also critical to the brain's adaptive response to ischemic stroke. They found that NANOG is preferentially expressed in undifferentiated neuronal cells, and is upregulated under hypoxic (low-oxygen) conditions following a stroke. The activity of Hif-1, a master regulator gene for a hypoxic response, boosts expression of the Nanog gene resulting in hypoxia-induced proliferation of neuronal progenitors. NANOG induction in neuronal progenitor cells trigger a cascade of changes across the brain, including regeneration of brain tissue after hypoxic injury. NANOG plays a key role in cellular plasticity and the acquisition of the stem cell state during reprogramming, but its role in the regenerative process remains unclear. Here, we show that the induction of NANOG in neuronal cells is necessary for the physiological initiation of neuronal regeneration in response to ischemic stress. Specifically, we found that NANOG was preferentially expressed in undifferentiated neuronal cells, and forced expression of Nanog in neural progenitor cells (NPCs) promoted their self-renewing expansion both in ex-vivo slice cultures and in vitro limiting dilution analysis. Notably, the upstream region of the Nanog gene contains sequence motifs for hypoxia-inducible factor-1 alpha (HIF-1 alpha). Therefore, cerebral neurons exposed to hypoxia significantly upregulated NANOG expression selectively in primitive (CD133(+)) cells, but not in mature cells, leading to the expansion of NPCs. Notably, up to 80% of the neuronal expansion induced by hypoxia was attributed to NANOG-expressing neuronal cells, whereas knockdown during hypoxia abolished this expansion and was accompanied by the downregulation of other pluripotency-related genes. Moreover, the number of NANOG-expressing neuronal cells were transiently increased in response to ischemic insult, predominantly in the infarct area of brain regions undergoing neurogenesis, but not in non-neurogenic loci. Together, these findings reveal a functional effect of NANOG-induction for the initiation of adaptive neuronal regeneration among heterogeneous NPC subsets, pointing to cellular plasticity as a potential link between regeneration and reprogramming processes.

Automated summary

This study reveals the crucial role of NANOG regulatory protein in neuronal regeneration after ischemic stroke, showing its induction can promote the expansion of neuronal cells and regeneration of brain tissue, suggesting cellular plasticity as a potential link between regeneration and reprogramming processes.