An NRF2 Perspective on Stem Cells and Ageing.

Matthew Dodson,Annadurai Anandhan,Donna D Zhang,Lalitha Madhavan

doi:10.3389/fragi.2021.690686

Abstract

Redox and metabolic mechanisms lie at the heart of stem cell survival and regenerative activity. NRF2 is a major transcriptional controller of cellular redox and metabolic homeostasis, which has also been implicated in ageing and lifespan regulation. However, NRF2’s role in stem cells and their functioning with age is only just emerging. Here, focusing mainly on neural stem cells, which are core to adult brain plasticity and function, we review recent findings that identify NRF2 as a fundamental player in stem cell biology and ageing. We also discuss NRF2-based molecular programs that may govern stem cell state and function with age, and implications of this for age-related pathologies.

Highlights

The importance of redox and metabolic states in regulating stem cell homeostasis has become increasingly clear in recent years (Folmes et al, 2012; Bigarella et al, 2014; Holmström and Finkel, 2014; Perales-Clemente et al, 2014)
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a member of a family of basic leucine transcription factors that binds to Antioxidant Response Elements (AREs) in the promoter region of genes involved in redox regulation, proteostasis, DNA repair, prevention of apoptosis, iron and heme metabolism, and phase I, II, and III drug/xenobiotic metabolism (Hayes and Dinkova-Kostova, 2014; Yamamoto et al, 2018; Dodson et al, 2019; Schmidlin et al, 2019)
In neural stem cells (NSCs), downregulation of NRF2 and upregulation of the NF-κB cascade promote differentiation, with the inverse promoting NSC self-renewal. This relationship may not hold true in other adult stem cell types, such as mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) where high NF-κB levels prevent differentiation; it is clear that NRF2 control of other transcriptional responses appears to play an integral role in dictating stem cell stemness, proliferation, and differentiation, in the context of NSC-driven neurogenesis

Summary

INTRODUCTION

The importance of redox and metabolic states in regulating stem cell homeostasis has become increasingly clear in recent years (Folmes et al, 2012; Bigarella et al, 2014; Holmström and Finkel, 2014; Perales-Clemente et al, 2014). With an emphasis on neural stem cells, we summarize and discuss recent findings on NRF2’s involvement in regulating stem cell fate and function during the normal lifespan and in the context of injury and age-related pathologies. This is a crucial topic to understand given the fundamental role of neural stem cells in adult neurogenesis as well as their relevance to age-related promotion of disease

Metabolic and Redox Regulation of Neural Stem Cells

CONCLUSION AND PERSPECTIVES