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Molecular regulation of stem cell quiescence

Nature Reviews Molecular Cell Biology volume 14, pages 329–340 (2013)Cite this article

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Key Points

  • In contrast to terminally differentiated cells that reside in an irreversible, post-mitotic G0 state of the cell cycle, subsets of mammalian adult stem cells reside in a reversible G0 state (which is also referred to as the quiescent state) for prolonged periods of time. The ability of stem cells to remain quiescent is critical for the maintenance of stem cell potency and for their function during tissue homeostasis and tissue repair in the event of an injury.

  • The quiescent state has long been viewed as a dormant state with minimal basal activity. Increasing evidence from mammalian stem cell systems suggests that various signalling pathways actively maintain the quiescent state.

  • The identification of quiescent stem cells has been hampered by their rarity in tissues. Traditionally, the identification of quiescent stem cells is based on label retention techniques. Recent advances in genetic lineage tracing approaches has allowed the characterization of quiescent and active stem cells in various tissues.

  • Quiescent stem cells have several protective mechanisms and mechanisms involved in the maintenance of stemness. To achieve the goal of maintaining a stem cell unperturbed, regulatory mechanisms are in place to respond to environmental stress, to regulate metabolism and to preserve genomic integrity.

  • The ability of stem cells to self-renew and replenish the quiescent stem cell pool in adult tissues subserves tissue homeostasis and assures tissue repair and regeneration in case of injury. Epigenetic, transcriptional and post-transcriptional mechanisms involving multiple regulators are in place to control these processes.

  • Quiescent stem cells respond to extrinsic stimuli rapidly for activation. How a quiescent stem cell responds to such stimuli is poorly understood. Signalling networks that regulate stem cell quiescence are integrated to allow rapid activation.

Abstract

Subsets of mammalian adult stem cells reside in the quiescent state for prolonged periods of time. This state, which is reversible, has long been viewed as dormant and with minimal basal activity. Recent advances in adult stem cell isolation have provided insights into the epigenetic, transcriptional and post-transcriptional control of quiescence and suggest that quiescence is an actively maintained state in which signalling pathways are involved in maintaining a poised state that allows rapid activation. Deciphering the molecular mechanisms regulating adult stem cell quiescence will increase our understanding of tissue regeneration mechanisms and how they are dysregulated in pathological conditions and in ageing.

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Figure 1: Molecular regulation of stem cell quiescence.
Figure 2: Survival mechanisms of quiescent and activated stem cells.
Figure 3: Quiescent stem cells are poised for activation.
Figure 4: Transcriptional control of stem cell quiescence.

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Acknowledgements

Research in the Rando laboratory is supported by awards from the Glenn Foundation for Medical Research, the US National Institutes of Health (P01 AG036695, R37 MERIT Award AG023806, R01 AR056849, and R01 AR062185), the Muscular Dystrophy Association and the Department of Veterans Affairs (Merit Review) to T.A.R.

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Author notes

  1. Thomas A. Rando

    Present address: Neurology Service and Rehabilitation Research and Development Center of Excellence, Veterans Affairs Palo Alto Health Care System, Palo Alto, 94304, California, USA

  2. Tom H. Cheung

    Present address: Present address: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.,

Authors and Affiliations

  1. Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, 94305, California, USA

    Tom H. Cheung & Thomas A. Rando

  2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, 94305, California, USA

    Tom H. Cheung & Thomas A. Rando

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Supplementary information

Supplementary information Table S1

Quiescent stem cell gene signature (PDF 122 kb)

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Glossary

Progenitor cell

Proliferating stem cell progeny that can differentiate into specific cell types.

Heterochronic parabiosis

Whereby an old animal is surgically connected to a young animal to promote the establishment of a single, shared circulatory system between the two.

Lineage tracing

The process of identifying all progeny of a single cell.

Transit amplifying progenitors

Progenitor cells that replicate rapidly with very short cell cycle times for progenitor cell expansion.

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Cheung, T., Rando, T. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol 14, 329–340 (2013). https://doi.org/10.1038/nrm3591

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