Metabolic regulation of the hallmarks of stem cell biology

Abstract

Stem cells perform many different functions, each of which requires specific metabolic adaptations. Over the past decades, studies of pluripotent and tissue stem cells have uncovered a range of metabolic preferences and strategies that correlate with or exert control over specific cell states. This review aims to describe the common themes that emerge from the study of stem cell metabolism: (1) metabolic pathways supporting stem cell proliferation, (2) metabolic pathways maintaining stem cell quiescence, (3) metabolic control of cellular stress responses and cell death, (4) metabolic regulation of stem cell identity, and (5) metabolic requirements of the stem cell niche.

Figure 1.. Metabolic support of stem cell functions.

While metabolism can vary dramatically between different stem cell types, several common themes have emerged in stem cell metabolism that support vital cellular functions. Specific metabolic strategies support stem cell proliferation (1) and quiescence (2). Metabolism is likewise involved in stem cell responses to cellular stressors and cell death (3). By influencing the deposition or removal of epigenetic modifications, metabolism can also control stem cell fate (4). Stem cells are also influenced by the metabolic requirements of their endogenous niche (5).

Figure 2.. Metabolic pathways supporting stem cell proliferation

Multiple metabolic pathways generate the building blocks required for stem cell proliferation. A) Diverse substrates fuel anabolic reactions that generate either metabolic intermediates or reducing equivalents (NADPH, NADH, FADH₂) for macromolecule synthesis. One major substrate is glucose, which is converted to pyruvate by glycolysis. Pyruvate can either be converted to lactate by LDH and discarded from the cell or can enter the TCA cycle where it is oxidized and generates reducing equivalents that power oxidative phosphorylation by the ETC. Regulation of oxidative metabolism is key to both PSC and tissue stem cell function. B) Many cellular oxidation reactions—including the oxidation of glucose—require NAD⁺ as a cofactor. Therefore, multiple metabolic pathways have evolved to regenerate NAD⁺ from NADH. Differential modes of NAD⁺ regeneration by either the LDH reaction or by cross-compartmental electron shuttles underlie stem cell identity.

Figure 3.. Metabolic strategies to support stem cell quiescence

Cell cycle exit in quiescence is supported by specific metabolic rewiring. Decreased metabolic demand (A) is achieved by altered metabolic gene expression, decreased metabolic pathway flux, and an overall reduction in metabolic outputs such as protein synthesis. In concert with decreased metabolic demand, increased cellular recycling processes (B) such as autophagy and lysosomal biogenesis liberate metabolites to support cellular bioenergetics and constrain mitochondrial respiration via mitophagy.

Figure 4.. Stem cell responses to cellular stress

Stem cells have distinct responses to cellular stress. While PSCs are resistant to cell death, tissue stem cell populations have increased propensity for cell death or differentiation in response to external stressors. Stem cells also have increased reliance on cellular detoxification and antioxidant pathways. Activation of the integrated stress response has also been linked to stem cell function and dysfunction in normal development and disease.

Figure 5.. Metabolic-chromatin crosstalk in stem cells

Metabolites form the chemical modifications that decorate chromatin and can regulate the activity of many chromatin-modifying enzymes to regulate stem cell fate. A) Cytosolic acetyl-CoA is the acetyl-donor for histone acetyltransferases and is largely generated either from mitochondrially-derived citrate by ACL or from acetate by ACSS2. Ketone bodies such as BHB have been shown to inhibit histone deacylases. B) Multiple amino acids can contribute to cellular pools of SAM, the methyl donor for histone and DNA methylation by methyltransferases. Demethylation is carried out by the family of α-KG-dependent-dioxygenases. Cellular levels of α-KG influence dioxygenase activity through its role as a co-substrate for demethylation reactions. Ascorbate is a cofactor that promotes the activity of the TET enzymes that iteratively oxidize methylated cytosines in DNA generate 5-hydroxymethylcytosine (5hmC) or its oxidized derivatives (5-formylcytosine or 5-carboxycytosine) that are intermediates in DNA demethylation.