2024 February 01 | Benjamin T. Jackson, Lydia W. S. Finley
Stem cells perform multiple functions, each requiring specific metabolic adaptations. Over the past decades, studies of pluripotent and tissue stem cells have revealed metabolic preferences and strategies that correlate with or control specific cell states. This review outlines five common themes in 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. Stem cells must balance self-renewal and differentiation, and their metabolic programs must be compatible with gene expression programs that control fate. Stem cells also have strategies to respond to stressors and resist cell death. Metabolic cues from their niche also influence their function. These considerations show that there is no unified formula for stem cell metabolism; rather, metabolic signatures vary with the identities and functional states of stem cells. Metabolic studies are challenging due to the rarity of stem cells and the need for large numbers for metabolomic studies. However, new sequencing approaches allow for single-cell gene expression analysis. Metabolic pathways used by stem cells can vary between cell types and are dynamically altered during differentiation. Aerobic glycolysis, often called the Warburg Effect, is a key feature of stem cells and cancer cells. The fate of pyruvate—whether it is excreted as lactate or used in the TCA cycle—is closely tied to cell state. In PSCs, pyruvate is preferentially incorporated into TCA cycle intermediates in the naive state. PSCs that exit the naive state show decreased glucose oxidation and increased lactate secretion. Aerobic glycolysis is not universally downregulated during differentiation, as human PSCs maintain high glycolytic flux when differentiated to ectoderm. The role of aerobic glycolysis in stem cells remains an open question. Metabolic pathways used by stem cells can vary between cell types and are dynamically altered during differentiation. Metabolic adaptations during quiescence are also important, as quiescent stem cells have lower metabolic activity and increased autophagy. Autophagy helps maintain stem cell quiescence by removing dysfunctional organelles and cellular debris. Lysosomal biogenesis is also important for maintaining quiescence, as quiescent HSCs have increased lysosomal activity and nuclear localization of TFEB. Resistance to metabolic stress and cell death is another key hallmark of stem cells. Stem cells must withstand some degree of cellular stress and have mechanisms to resist cell death. The integrated stress response (ISR) is a pathway that responds to various cellular stresses, including mitochondrial dysfunction and oxidative stress. ISR activation can lead to selective translation of proteins that support stem cell maintenance. Antioxidant and detoxification pathways are also important for stem cell survival, as ROS can be cytotoxic and genotoxic. Stem cells regulate ROS levels to maintain genetic integrity and support selfStem cells perform multiple functions, each requiring specific metabolic adaptations. Over the past decades, studies of pluripotent and tissue stem cells have revealed metabolic preferences and strategies that correlate with or control specific cell states. This review outlines five common themes in 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. Stem cells must balance self-renewal and differentiation, and their metabolic programs must be compatible with gene expression programs that control fate. Stem cells also have strategies to respond to stressors and resist cell death. Metabolic cues from their niche also influence their function. These considerations show that there is no unified formula for stem cell metabolism; rather, metabolic signatures vary with the identities and functional states of stem cells. Metabolic studies are challenging due to the rarity of stem cells and the need for large numbers for metabolomic studies. However, new sequencing approaches allow for single-cell gene expression analysis. Metabolic pathways used by stem cells can vary between cell types and are dynamically altered during differentiation. Aerobic glycolysis, often called the Warburg Effect, is a key feature of stem cells and cancer cells. The fate of pyruvate—whether it is excreted as lactate or used in the TCA cycle—is closely tied to cell state. In PSCs, pyruvate is preferentially incorporated into TCA cycle intermediates in the naive state. PSCs that exit the naive state show decreased glucose oxidation and increased lactate secretion. Aerobic glycolysis is not universally downregulated during differentiation, as human PSCs maintain high glycolytic flux when differentiated to ectoderm. The role of aerobic glycolysis in stem cells remains an open question. Metabolic pathways used by stem cells can vary between cell types and are dynamically altered during differentiation. Metabolic adaptations during quiescence are also important, as quiescent stem cells have lower metabolic activity and increased autophagy. Autophagy helps maintain stem cell quiescence by removing dysfunctional organelles and cellular debris. Lysosomal biogenesis is also important for maintaining quiescence, as quiescent HSCs have increased lysosomal activity and nuclear localization of TFEB. Resistance to metabolic stress and cell death is another key hallmark of stem cells. Stem cells must withstand some degree of cellular stress and have mechanisms to resist cell death. The integrated stress response (ISR) is a pathway that responds to various cellular stresses, including mitochondrial dysfunction and oxidative stress. ISR activation can lead to selective translation of proteins that support stem cell maintenance. Antioxidant and detoxification pathways are also important for stem cell survival, as ROS can be cytotoxic and genotoxic. Stem cells regulate ROS levels to maintain genetic integrity and support self