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Review
. 2019 Jun 11;12(6):1190-1200.
doi: 10.1016/j.stemcr.2019.05.012.

Mechanisms, Hallmarks, and Implications of Stem Cell Quiescence

Inchul J Cho  1 , Prudence PokWai Lui  1 , Jana Obajdin  1 , Federica Riccio  1 , Wladislaw Stroukov  1 , Thea Louise Willis  1 , Francesca Spagnoli  1 , Fiona M Watt  2
Affiliations
Review

Mechanisms, Hallmarks, and Implications of Stem Cell Quiescence

Inchul J Cho et al. Stem Cell Reports. .

Abstract

Cellular quiescence is a dormant but reversible cellular state in which cell-cycle entry and proliferation are prevented. Recent studies both in vivo and in vitro demonstrate that quiescence is actively maintained through synergistic interactions between intrinsic and extrinsic signals. Subtypes of adult mammalian stem cells can be maintained in this poised, quiescent state, and subsequently reactivated upon tissue injury to restore homeostasis. However, quiescence can become deregulated in pathological settings. In this review, we discuss the recent advances uncovering intracellular signaling pathways, transcriptional changes, and extracellular cues within the stem cell niche that control induction and exit from quiescence in tissue stem cells. We discuss the implications of quiescence as well as the pharmacological and genetic approaches that are being explored to either induce or prevent quiescence as a therapeutic strategy.

Keywords: autophagy; cancer; cell cycle; cell therapy; niche; quiescence; stem cells.

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Figures

Figure 1
Figure 1
Quiescence (G0) Quiescence is a reversible G0 state, because cells retain the ability to re-enter G1 of the cell cycle after passing the restriction point (R-point) of the G1/S transition. Cells in G1 can also enter senescence, which is an irreversible state. E2F mediates transcription of cell-cycle genes. In quiescent cells, E2F is repressed by retinoblastoma (RB) binding. The repressive ability of RB is regulated by the CDK/cyclin complex, which in turn is controlled by CDK/cyclin inhibitors. Adapted from Biggar and Storey (2009).
Figure 2
Figure 2
Intracellular Mechanisms Regulating Quiescence (A) Autophagy is an intracellular metabolic process characterized by the nucleation of a double-membrane vesicle termed the phagophore, which matures into the autophagosome. (B) Quiescence can be positively regulated by miRNA molecules that are produced by the endoribonuclease Dicer. miRNAs can bind the 3′ untranslated region (UTR) (blue) or 5′ seed region (red) of mRNA. Reduction in mRNA 3′ UTR length results in a release from miRNA inhibition. Sequestration of Myf5 and DEK, proteins promoting differentiation and proliferation respectively, occurs in quiescent muscle stem cells through messenger ribonucleoprotein (mRNP) granules that contain miRNAs such as miR-489 and miR-31.
Figure 3
Figure 3
Microenvironmental Regulators of Quiescence (A) The stem cell microenvironment comprises multiple components, including direct interactions with neighboring cells, soluble factors, and binding sites on ECM proteins. Stem cells transduce those cues via their surface receptors and integrate the signals in complex intracellular regulatory networks. (B) In one example of microenvironmental modulation of quiescence, muscle stem cells secrete collagen V, which can act reciprocally via the calcitonin receptor (CALCR) to maintain quiescence.
Figure 4
Figure 4
Modulation of Stem Cell Quiescence for Therapeutic Benefit “Lock-out” strategies consist of forcing stem cells out of quiescence to promote proliferation and differentiation. “Lock-in” strategies consist of re-establishing or maintaining the quiescent state to prevent aberrant proliferation and differentiation or premature senescence.
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