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Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity

Nature Reviews Molecular Cell Biology volume 24, pages 334–354 (2023)Cite this article

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Abstract

Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.

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Fig. 1: Types of quiescent stem cells and their features.
Fig. 2: Key signalling pathways of quiescence maintenance, exit or entry.
Fig. 3: Stem cell quiescence and the cell cycle.
Fig. 4: Nuclear post-transcriptional mechanisms that control stem cell quiescence.
Fig. 5: Cytoplasmic post-transcriptional mechanisms that control stem cell quiescence.
Fig. 6: Post-translational mechanisms that control stem cell quiescence.

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Acknowledgements

This work was supported by Novo NordiskFonden Start Package grant 0071116 (A.D.M.) and National Institutes of Health grants P01 AG036695, R01 AG068667, and R01 AR073248 (T.A.R.).

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  1. Antoine de Morree

    Present address: Department of Biomedicine, Aarhus University, Aarhus, Denmark

  2. Thomas A. Rando

    Present address: Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA

Authors and Affiliations

  1. Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA

    Antoine de Morree & Thomas A. Rando

  2. Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA

    Antoine de Morree & Thomas A. Rando

  3. Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Thomas A. Rando

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Glossary

Adult stem cells

Rare populations of cells that are found in the body throughout most of postnatal life and that give rise to a limited number of mature cell types that build the tissue in which they reside.

ATR

A serine/threonine-protein kinase that senses persistent single-stranded DNA and activates a DNA damage checkpoint, leading to cell cycle arrest.

Autologous stem cell transplantation therapies

Procedures in which stem cells are isolated from a person and placed back following expansion and/or modification such as gene correction.

Bulge

Morphologically distinct area in the hair follicle in between the opening of a sebaceous gland and the attachment site of the arrector pili muscle that functions as the hair follicle stem cell niche.

Cancer stem cells

Cancer cells with stem cell properties such as self-renewal; some cancer stem cells can adopt a quiescent state.

Embryonic stem cells

Cells derived from the blastocyst of the embryo and able to form all tissue lineages.

Endoplasmic reticulum-associated degradation

A pathway that targets misfolded proteins in the endoplasmic reticulum for ubiquitination and proteasomal degradation.

Exon-junction complex

Protein complex that forms on a pre-mRNA strand at the junction of two exons immediately after splicing.

Germ line stem cells

Cells that can generate the haploid gametes.

Induced pluripotent stem cells

Cells created from somatic cells through the overexpression of specific transcription factors, rendering them immortal and able to form all tissue lineages.

Non-homologous end joining

A mechanism of DNA double-strand break repair without the need for a homologous template.

Processing bodies

Cytoplasmic ribonucleoprotein granules primarily composed of translationally repressed mRNAs.

RNA granules

Non-membrane-bound organelles composed of RNA and protein.

Stem cell activation

The process by which a quiescent stem cell exits the quiescent state and enters the cell cycle.

Trithorax group

A family of proteins that modify or remodel histones to activate genes and keep them active.

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de Morree, A., Rando, T.A. Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity. Nat Rev Mol Cell Biol 24, 334–354 (2023). https://doi.org/10.1038/s41580-022-00568-6

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