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A Role for Nrf2 Expression in Defining the Aging of Hippocampal Neural Stem Cells.

ABSTRACT: Redox mechanisms are emerging as essential to stem cell function given their capacity to influence a number of important signaling pathways governing stem cell survival and regenerative activity. In this context, our recent work identified the reduced expression of nuclear factor (erythroid-derived 2)-like 2, or Nrf2, in mediating the decline in subventricular zone neural stem progenitor cell (NSPC) regeneration during aging. Since Nrf2 is a major transcription factor at the heart of cellular redox regulation and homeostasis, the current study investigates the role that it may play in the aging of NSPCs that reside within the other major mammalian germinal niche located in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. Using rats from multiple aging stages ranging from newborn to old age, and aging Nrf2 knockout mice, we first determined that, in contrast with subventricular zone (SVZ) NSPCs, Nrf2 expression does not significantly affect overall DG NSPC viability with age. However, DG NSPCs resembled SVZ stem cells, in that Nrf2 expression controlled their proliferation and the balance of neuronal versus glial differentiation particularly in relation to a specific critical period during middle age. Also, importantly, this Nrf2-based control of NSPC regeneration was found to impact functional neurogenesis-related hippocampal behaviors, particularly in the Morris water maze and in pattern separation tasks. Furthermore, the enrichment of the hippocampal environment via the transplantation of Nrf2-overexpressing NSPCs was able to mitigate the age-related decline in DG stem cell regeneration during the critical middle-age period, and significantly improved pattern separation abilities. In summary, these results emphasize the importance of Nrf2 in DG NSPC regeneration, and support Nrf2 upregulation as a potential approach to advantageously modulate DG NSPC activity with age.

SUBMITTER: Ray S

PROVIDER: S-EPMC6041888 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A Role for Nrf2 Expression in Defining the Aging of Hippocampal Neural Stem Cells.

Ray S S Corenblum M J MJ Anandhan A A Reed A A Ortiz F O FO Zhang D D DD Barnes C A CA Madhavan L L

Cell transplantation 20180401 4

Redox mechanisms are emerging as essential to stem cell function given their capacity to influence a number of important signaling pathways governing stem cell survival and regenerative activity. In this context, our recent work identified the reduced expression of nuclear factor (erythroid-derived 2)-like 2, or Nrf2, in mediating the decline in subventricular zone neural stem progenitor cell (NSPC) regeneration during aging. Since Nrf2 is a major transcription factor at the heart of cellular re ...[more]

PMID: 29871525

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Project description:BackgroundIn the brain of adult mammals, neural stem cells persist in the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus, which are specialized niches with proliferative capacity. Most neural stem cells are in a quiescent state, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to produce new neurons, so neural stem cells are considered to be a potential source for cell replacement therapy of many nervous system diseases. We characterized the expression of Ndel1 during the differentiation of neural stem cells induced by hippocampus exosomes, and assessed the effect of Ndel1 on neural stem cells differentiation.MethodsHippocampal exosomes were isolated and extracted, and co-cultured exosomes with neural stem cells. Western blot, flow cytometry, and immunofluorescence analyses were used to analyze expression of neuronal markers. Further, utilizing high-throughput RNA sequencing technology, we found that nudE neurodevelopment protein 1-like 1 was significantly upregulated in exosomes derived from denervated hippocampus, and then characterized its mechanism and function during neural stem cells differentiation by qRT-PCR, western blot, flow cytometry, and immunofluorescence analyses.ResultsOur results revealed that exosomes of denervated hippocampus promoted the differentiation of neural stem cells into neuron. Hence, we identified that nudE neurodevelopment protein 1-like 1 was significantly upregulated and highly expressed in the nervous system. In addition, we found that miR-107-3p may regulate neural stem cell differentiation by targeting Ndel1.ConclusionsOur results revealed that deafferentation of the hippocampal exosomes co-cultured with neural stem cells could promote them to differentiate into neurons. Hence, we found that miR-107-3p may regulate neural stem cells differentiation by targeting Ndel1. Importantly, Ndel1 enhanced spatial learning and hippocampal neurogenesis in rats after fimbria fornix transection in vivo. These findings set the stage for a better understanding of neurogenesis, a process that 1 day may inspire new treatments for central nervous system diseases.

Dataset Information

A Role for Nrf2 Expression in Defining the Aging of Hippocampal Neural Stem Cells.

Publications

A Role for Nrf2 Expression in Defining the Aging of Hippocampal Neural Stem Cells.

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