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Metabolic regulation of somatic stem cells in vivo

Abstract

Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.

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Fig. 1: Approaches for the analysis of stem cell metabolism: metabolomics and isotope tracing.
Fig. 2: Metabolic regulation of quiescent and activated haematopoietic stem cells.
Fig. 3: Autophagy and lysosome function in stem cells enforce quiescence and promotes the maintenance of self-renewal potential.

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Acknowledgements

The authors thank M. Agathocleous for commenting on the manuscript and P. Mishra for discussions related to mitochondrial function. S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Paediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Paediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. This work was supported partly by the National Institutes of Health (NIH) (DK118745 to S.J.M.). C.E.M. was supported by a Postdoctoral Fellowship from the American Cancer Society (PF-13-245-01-LIB). A.W.D. was supported by a Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship from the National Heart, Lung, and Blood Institute (NHLBI) (F32HL135975).

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C.E.M. drafted the main text and A.W.D. drafted the figures and the glossary. S.J.M. then worked with C.E.M. to revise the text and with A.W.D. to revise the figures. All authors reviewed the manuscript before submission.

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Correspondence to Sean J. Morrison.

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Nature Reviews Molecular Cell Biology thanks Navdeep Chandel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Hypoxia-inducible transcription factors

(HIF1α, HIF2α). Transcription factors that are degraded by the proteasome under normoxic conditions but are stabilized and translocated to the nucleus in response to low oxygen tension to promote the transcription of genes that mitigate hypoxic stress.

Ten–eleven translocation (TET) family DNA demethylases

Enzymes that mediate DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine.

Jumonji C histone demethylases

Enzymes that remove methyl groups from histones and other proteins.

Reactive oxygen species

(ROS). Highly reactive oxygen-containing molecules, including superoxide radicals, hydroxyl radicals and hydrogen peroxide, that are formed partly as a result of the leakage of electrons from the electron transport chain.

Mitochondrial pyruvate carrier 1

(MPC1). One subunit of the mitochondrial pyruvate transporter (MPC), which is localized to the mitochondrial inner membrane and facilitates pyruvate entry into the mitochondrial matrix.

Lactate dehydrogenase A

(LDHA). An enzyme that catalyses the reversible conversion of pyruvate and NADH to lactate and nicotinamide adenine dinucleotide (NAD+).

Sirtuin 1

(SIRT1). A nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that removes acetyl groups from histones and other proteins.

Pyruvate dehydrogenase kinase

(PDK2, PDK4). An enzyme that inactivates pyruvate dehydrogenase via phosphorylation, restricting the availability of acetyl-CoA for the tricarboxylic acid (TCA) cycle.

Dentate gyrus

A region of the hippocampus that maintains neural stem cells and neurogenesis in the adult mouse brain.

Electron transport chain

A series of protein complexes that transfer electrons within the inner mitochondrial membrane while transporting protons out of the inner mitochondrial space, creating a membrane potential. The return of these protons to the inner mitochondrial space via ATP synthase generates ATP.

Mitochondrial membrane potential

A proton gradient that is generated across the inner mitochondrial membrane as a result of electron transport chain activity. Increased mitochondrial membrane potential generally reflects increased electron transport chain activity.

Multidrug-resistance pumps

Low-specificity transporters in the plasma membrane that mediate the removal of various cytotoxic small molecules from cells.

Ferroptotic cell death

A form of cell death marked by accumulation of lipid peroxides.

Mitochondrial uncoupling agent

A small molecule or protein that dissociates mitochondrial membrane potential from ATP production by facilitating the passage of protons through the mitochondrial membrane via mechanisms independent of ATP synthase.

Extracellular flux assays

Assays performed in culture that measure the oxygen consumption rate and extracellular acidification rate of live cells in real time, providing insight into the capacity of cells to undergo oxidative phosphorylation and glycolysis.

Metabolic flux analysis

A measurement of the rate at which enzymatic reactions occur in metabolic pathways in cells, often by measuring the rates at which isotopically labelled substrates are converted into other products.

Protein mitochondrial phosphatase

(PTPMT1). A phosphatase localized to the mitochondrial inner membrane that is necessary for the biosynthesis of cardiolipin, a phospholipid that promotes the activity of many mitochondrial membrane complexes including the electron transport chain.

Fumarate hydratase 1

(FH1). An enzyme that catalyses the reversible conversion of fumarate to malate.

Pyruvate kinase M2

(PKM2). An enzyme that catalyses the last and rate-limiting step in glycolysis, the conversion of phosphoenolpyruvate to pyruvate.

Cytochrome c oxidase

(COX). An enzyme that is a component of the electron transport chain complex IV that translocates protons across the inner mitochondrial membrane, increasing mitochondrial membrane potential.

Ataxia telangiectasia mutated

(ATM). A serine/threonine kinase that is recruited to sites of DNA double-strand breaks and initiates cell cycle arrest and DNA repair.

Lysine-specific methyltransferase 2E

(KTM2E or MLL5). An atypical member of the mixed-lineage leukaemia (MLL) family that lacks methyltransferase activity but is required for DNA double-strand break repair and normal cell cycle progression.

Tuberous sclerosis complex subunit 1

(TSC1). An inhibitor of signalling by the mammalian target of rapamycin complex 1 (mTORC1).

Forkhead box O

(FOXO). A family of transcription factors that regulate the expression of genes that control many aspects of cellular and tissue homeostasis including cell cycle progression, metabolism and redox balance.

NF-E2-related factor 2

(NFE2L2 or NRF2). A transcription factor that is activated by reactive oxygen species (ROS) and that promotes the transcription of genes that encode antioxidant enzymes.

Fanconi anaemia DNA repair pathway

DNA repair proteins that are required to repair inter-strand cross links and to prevent bone marrow failure and leukaemia.

Liver kinase B1

(STK11 or LKB1). A serine/threonine kinase that activates AMP family kinases, including AMPK, a metabolic checkpoint that inhibits anabolic pathways and promotes glucose and fatty acid uptake in response to low ATP levels.

Phosphatase and tensin homologue

(PTEN). A tumour suppressor that inhibits AKT activation by dephosphorylating phosphatidylinositol triphosphate (PIP3).

4E-binding proteins

(4E-BP1, 4E-BP2). Proteins that inhibit translation by binding and inhibiting the eukaryotic translation initiation factor eIF4E.

Eukaryotic translation initiation factor 2A

(EIF2A). A subunit of the eukaryotic translation initiation factor 2 (eIF2) complex that promotes translation initiation by promoting the binding of methionine tRNAs to ribosomes and whose function is inhibited by phosphorylation.

Integrated stress response

A signalling network in eukaryotic cells that reduces protein translation and is activated by various cellular stresses including hypoxia, nutrient deprivation, accumulation of unfolded proteins and oncogene activation.

Proteotoxic stress

Cellular stress that is induced by the accumulation of misfolded or damaged proteins by heat shock, proteasome inhibition, translational infidelity, oxidative stress or accumulation of insoluble protein aggregates.

Sphingolipids

A diverse class of lipid signalling molecules that include ceramide, sphingosine and sphingosine-1-phosphate.

p38 MAP kinase

A kinase (encoded by the MAPK14 gene) that is activated by cellular stresses and pro-inflammatory cytokines.

Branched-chain aminotransferase 1

(BCAT1). An enzyme that catalyses the reversible transamination of branched-chain keto acids to the branched-chain amino acids valine, leucine and isoleucine.

Mammalian target of rapamycin complex 1

(mTORC1). A multiprotein complex that senses intracellular nutrient availability and phosphorylates substrates that promote anabolic pathways and cell cycle progression.

Fatty acid oxidation

Catabolism of fatty acids into acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle and generate ATP.

Autophagy

A cellular recycling pathway in which cellular components are engulfed in a vesicle known as an autophagosome, which delivers those components to a lysosome for degradation into macromolecule precursors (that is, amino acids and nucleotides).

ATG7

An E1 ligase-like enzyme that is required for autophagosome formation.

ATG12

A ubiquitin-like modifier that is conjugated to ATG5 and is critical for the formation of the early autophagosome.

Stem cell factor

(SCF). A growth factor that is required for the maintenance of haematopoietic stem cells (HSCs) and is produced by bone marrow stromal cells, bone marrow endothelial cells and bone marrow adipocytes.

Clonal haematopoiesis

A preleukaemic condition in which a mutant clone of HSCs outcompetes other HSCs and contributes disproportionately to haematopoiesis.

Retinoic acid

The bioactive metabolite of vitamin A that mediates vitamin A functions.

Ketone bodies

Metabolites containing a ketone group that are produced from fatty acids in the liver and can be converted to acetyl-CoA for oxidation in the tricarboxylic acid (TCA) cycle.

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Meacham, C.E., DeVilbiss, A.W. & Morrison, S.J. Metabolic regulation of somatic stem cells in vivo. Nat Rev Mol Cell Biol 23, 428–443 (2022). https://doi.org/10.1038/s41580-022-00462-1

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