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Metabolic requirements for the maintenance of self-renewing stem cells

Nature Reviews Molecular Cell Biology volume 15, pages 243–256 (2014)Cite this article

Subjects

Key Points

  • Stem cells perpetuate themselves through self-renewal and they replenish mature cells to maintain tissue homeostasis throughout the lifespan of an organism.

  • Stem cell function is precisely regulated by various intrinsic mechanisms, in coordination with extrinsic stimuli; recent studies have revealed critical roles for stem cell metabolism in maintaining stem cell self-renewal.

  • Stem cells reside within specialized niches (for example, a hypoxic niche), where specific local conditions have a role in maintaining a quiescent state that is essential for preserving the self-renewal capacity of stem cells.

  • Many types of stem cells heavily rely on anaerobic glycolysis, rather than mitochondrial oxidative phosphorylation, to produce the low levels of intracellular reactive oxygen species, which inhibit stem cell ageing.

  • The balance between stem cell quiescence and proliferation is regulated by the nutrient-sensitive PI3K–AKT–mTOR and AMPK pathways, and Gln metabolism.

  • Recent studies have uncovered a crucial role for fatty acid metabolism in the self-renewal of haematopoietic stem cells (HSCs) through the control it exerts over stem cell fate decisions.

Abstract

A distinctive feature of stem cells is their capacity to self-renew to maintain pluripotency. Studies of genetically-engineered mouse models and recent advances in metabolomic analysis, particularly in haematopoietic stem cells, have deepened our understanding of the contribution made by metabolic cues to the regulation of stem cell self-renewal. Many types of stem cells heavily rely on anaerobic glycolysis, and stem cell function is also regulated by bioenergetic signalling, the AKT–mTOR pathway, Gln metabolism and fatty acid metabolism. As maintenance of a stem cell pool requires a finely-tuned balance between self-renewal and differentiation, investigations into the molecular mechanisms and metabolic pathways underlying these decisions hold great therapeutic promise.

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Figure 1: Two specific potentials and cell fates of stem cells.
Figure 2: Glycolysis and hypoxia-inducible factor 1α.
Figure 3: Overview of metabolic requirements in stem cells.
Figure 4: A ROS rheostat tightly regulates cellular ROS to maintain stemness and inhibit stem cell ageing.
Figure 5: Coordinated regulation of stem cell function by metabolism.

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Acknowledgements

The authors thank C. Lin, A. Sasaki and A. Carracedo Pérez for their comments and discussion on metabolic pathways in stem cells. T.S. is supported by the Seventh Framework Programme of the European Union under grant agreement number 306240 (SystemAge) and a Grant-in-Aid from the Japan Society for the Promotion of Science. K.I. is supported by grants from the US National Institutes of Health (NIH) (R00CA139009 and R01DK98263). The authors apologize to those whose work could not be discussed owing to space limitations.

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Authors and Affiliations

  1. Departments of Cell Biology/Stem Cell Institute and Medicine, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Keisuke Ito

  2. Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Tokyo, 160–8582, Japan

    Toshio Suda

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  1. Keisuke Ito
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Correspondence to Keisuke Ito or Toshio Suda.

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FURTHER INFORMATION

Oncomine

PowerPoint slides

Glossary

Self-renewal

The capacity to propagate stem cells with a differentiation potential (potency) that is similar to that of the mother stem cell.

Asymmetric cell division

One of the proposed models to explain the regulation of cell-fate decisions, which play a crucial part in stem cell self-renewal. During asymmetric division, on daughter cell remains a stem cell, while the other one becomes committed.

Hypoxia

A state of reduced oxygen pressure below a certain threshold, which restricts the function of organs, tissues or cells. It has a role in regulating stem cell behaviour. A partial oxygen pressure (PO2) of <40 mm Hg in arterial blood constitutes hypoxia.

Glycolysis

A metabolic pathway that generates ATP and converts one molecule of glucose into two molecules of pyruvate or lactate. Glycolysis occurs in the presence (aerobic glycolysis) or absence (anaerobic glycolysis) of oxygen.

Long-term HSCs

(LT-HSCs).Haematopoietic stem cells (HSCs) that are defined functionally by their ability to mediate the long-term repopulation of all haematopoietic lineages (known as long-term repopulating activity) after transfer to lethally irradiated recipients.

Pimonidazole

An effective and non-toxic exogenous 2-nitroimidazole marker for hypoxia. It forms adducts with thiol groups in proteins, peptides and amino acids specifically in hypoxic cells.

Oxidative phosphorylation

(OXPHOS). The mitochondrial reactions that generate and harness energy released from the oxidation of nutrients such as pyruvate, through a proton gradient, to synthesize ATP.

Normoxic conditions

Normal partial oxygen pressure (PO2) levels range from 150 mm Hg in the upper airway to ∼5 mm Hg in the retina.

Tricarboxylic acid cycle

(TCA cycle). Also known as the citric acid cycle and Krebs cycle. Cyclic series of enzyme-catalysed chemical reactions that form a key part of aerobic respiration in cells. Each complete turn of the cycle generates one GTP, two CO2, one FADH2 and three NADH molecules.

Reactive oxygen species

(ROS). Reactive molecules, such as hydrogen peroxide and superoxide anion. ROS form as by-products of cellular respiration and ionizing radiation, and are potentially damaging to cell structures and other molecules causing oxidative stress.

Membrane potential

An important parameter of mitochondrial function that is crucial for maintaining the physiological function of the respiratory chain to generate ATP. A great loss of the membrane potential renders cells depleted of energy, followed by death.

Metabolic reprogramming

Stem cell-specific programmes that may drive the dependency of stem cells on specific nutrients, such as glucose, fatty acids and Gln, as well as impose changes to the wiring of metabolic pathways to maintain stemness.

Catabolism

A set of metabolic pathways that breaks down molecules (for example, nucleic acids, lipids and proteins) into smaller units (for example, nucleotides, fatty acids and amino acids) to release energy.

Cristae

Folds in the inner membrane of mitochondria, which are studded with proteins, such as ATP synthase, and which increase the surface area for chemical reactions to occur (for example, cellular respiration).

p38 MAPK

A member of the MAPK family that is activated by various environmental stresses and inflammatory cytokines. It is involved in processes such as cell differentiation, apoptosis and autophagy.

p16

(also known as INK4A; encoded by CDKN2A). A tumour suppressor protein, which inhibits the activities of CDK4 and CDK6. This leads to cell cycle arrest and has key roles in important cellular physiological processes such as senescence and apoptosis.

Oncogene-induced senescence

(OIS). A tumour suppressor mechanism that prevents the expansion of cells bearing activated oncogenes, which is caused by aberrant activation of oncoproteins and tumour suppressors.

Pancytopenia

An abnormal reduction in the number of erythrocytes, leukocytes and platelets in the blood.

Glutaminolysis

Biochemical reactions in which Gln is broken down to Glu, Asp, CO2, pyruvate, lactate, Ala and citrate.

Fatty acid oxidation

(FAO). The dehydrogenation, hydration, oxidation and thiolysis reactions that cleave off the two-carbon acetyl-coenzyme A (CoA) from fatty acids, which then feeds into the tricarboxylic acid cycle (TCA) cycle. It also includes the generation of NADH and FADH2, which are used by the electron transport chain.

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Ito, K., Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15, 243–256 (2014). https://doi.org/10.1038/nrm3772

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