Redox homeostasis: the linchpin in stem cell self-renewal and differentiation

Abstract

Stem cells are characterized by their unique ability of self-renewal to maintain the so-called stem cell pool. Over the past decades, reactive oxygen species (ROS) have been recognized as toxic aerobic metabolism byproducts that are harmful to stem cells, leading to DNA damage, senescence or cell death. Recently, a growing body of literature has shown that stem cells reside in redox niches with low ROS levels. The balance of Redox homeostasis facilitates stem cell self-renewal by an intricate network. Thus, to fully decipher the underlying molecular mechanisms involved in the maintenance of stem cell self-renewal, it is critical to address the important role of redox homeostasis in the regulation of self-renewal and differentiation of stem cells. In this regard, we will discuss the regulatory mechanisms involved in the subtly orchestrated balance of redox status in stem cells by scavenger antioxidant enzyme systems that are well monitored by the hypoxia niches and crucial redox regulators including forkhead homeobox type O family (FoxOs), apurinic/apyrimidinic (AP) endonuclease1/redox factor-1 (APE1/Ref-1), nuclear factor erythroid-2-related factor 2 (Nrf2) and ataxia telangiectasia mutated (ATM). We will also introduce several pivotal ROS-sensitive molecules, such as hypoxia-inducible factors, p38 mitogen-activated protein kinase (p38) and p53, involved in the redox-regulated stem cell self-renewal. Specifically, all the aforementioned molecules can act as ‘redox sensors' by virtue of redox modifications of their cysteine residues, which are critically important in the control of protein function. Given the importance of redox homeostasis in the regulation of stem cell self-renewal, understanding the underlying molecular mechanisms involved will provide important new insights into stem cell biology.

Neuroprotection requires the functions of the RNA-binding protein HuR

“…On the other hand, the underrepresentation of genes transcribed by the metabolic transcription factor FOXO1 point towards a connection to PGC1 activity as it can physically interact with PGC1α 76 and can also be involved in several facets of oxidative damage control. 77 HuR affects also the mRNAs of pleiotropic factors whose excess in HT-22 cells and primary neurons may cause further damage or alter differentiation programs. For example, Myc can promote cell survival but its excess can lead to transformation or death.…”

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

“…The cellular redox status is crucial to the balance between stem/progenitor self-renewal and differentiation in various tissues [50]. Androgen deprivation causes an increase in reactive oxygen species and oxidative stress in the prostate [51], which may strongly activate stem/progenitor cells in the Abcg2 null prostate.…”

Reliability of ROS and RNS detection in hematopoietic stem cells − potential issues with probes and target cell population

“…However, ROS and RNS are not single entities but a broad range of chemically distinct reactive species with diverse biological reactivities (Nathan and Cunningham-Bussel, 2013). There are several intracellular sources of ROS, including the mitochondrial electron transport chain (ETC), the membrane-bound NADPH oxidase (NOX) complex, the endoplasmic reticulum, oxidoreductase enzymes and metal-catalyzed oxidation reactions (Nathan and Cunningham-Bussel, 2013;Wang et al, 2013) (Fig. 1) (Wardman, 2007;Winterbourn, 2014).…”

“…These include members of the polycomb family of proteins, such as B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) and PRdomain-containing 16 (Prdm-16), as well as regulators of the DNA damage response, for example apurinic/apyrimidinic (AP) endonuclease1/redox factor-1 and redox regulator nuclear factor erythroid-2-related factor 2 (Nrf2) (Alfadda and Sallam, 2012;Chuikov et al, 2010;Liu et al, 2009;Wang et al, 2013). …”

“…HSCs, and stem cells in general (Han et al, 2008), are highly vulnerable to increased levels of reactive oxygen species (ROS), whereas committed hematopoietic progenitor cells (HPCs) are not (Chen et al, 2008b;Ito et al, 2004;Jang and Sharkis, 2007). Nevertheless, an appropriate production of ROS is required for HSC functions, such as mobilization, survival, differentiation and proliferation (Guzy and Schumacker, 2006;Hole et al, 2010;Hosokawa et al, 2007;Jang and Sharkis, 2007;Sattler et al, 1999;Tesio et al, 2011;Wang et al, 2013). Furthermore, ROS modify gene expression and the activity of key metabolic regulators, thereby determining specific metabolic patterns and cell-fate decision (Bigarella et al, 2014).…”