Adult stem cells residing in mammalian tissues are unique in their abilities to maintain tissue homeostasis and to retain their stem cell identity via the process of self-renewal. Most adult tissues contain resident stem cells to compensate for tissue loss in normal homeostasis or in case of injury throughout the life of the organism. A subset of resident stem cells resides in the quiescent state for a prolonged period of time. Stem cells residing in the quiescent state, or sometimes referred to as reserve stem cells, are crucial for tissue maintenance as dysregulation or loss of stem cell quiescence often results in the depletion of stem cell pool in various tissues (Figure 1).
Figure 1. Quiescent stem cells are poised for activation. A proposed model of how a quiescent stem cell constitutes a poised state for activation. The epigenetic landscape keeps the chromatin in a permissive state whereas additional layers of transcriptional and post-transcriptional control fine- tune the quiescent stem cells to precise stem cell activation when needed. (Adapted from Nature Reviews Molecular Cell Biology, Cheung and Rando, 2013)
Previously, it was thought that quiescence is a state of inactivity and cells become quiescent as environmental conditions become suboptimal for cell proliferation. However, the concept of cellular quiescence has changed recently. Recent discoveries in stem cell biology suggest the notion that the state of quiescence is actively regulated and poised for action. Using next-generation sequencing techniques, my laboratory has begun to investigate how the quiescent stem cells are regulated at the epigenetic, transcriptional and post-transcriptional levels. It appears that stem cells adopt the quiescent state to preserve important functions such as stemness. During organismal ageing, quiescent stem cells are subjected to chronological ageing and result in a functional decline due to changes in microenvironment that governs stem cell maintenance or stem cell fate. It has been demonstrated that aged stem cells divide more frequently in low turnover tissue due to the disruption of stem cell quiescence. Taken together, quiescence is an important cellular state that is actively regulated. However, our understanding of this important cellular state is limited due to the rarity of this cell population. As stem cells residing in this state possess important functions, a better understanding of the molecular regulation of stem cell quiescence will provide important insights into the design of new therapeutic approaches based on enhancing stem cell functionality.
Mueller AA, van Velthoven CT, Fukumoto KD, Cheung TH and Rando TA.
Intronic Polyadenylation of PDGFRa in resident stem cells attenuates muscle fibrosis.
Nature. 2016 Nov 28. doi: 10.1038/nature20160.
Zhu H, Xiao F, Wang G, Wei X, Jiang L, Chen Y, Zhu L, Wang H, Diao Y, Wang H, Ip NY, Cheung TH, Wu Z.
STAT3 Regulates Self-Renewal of Adult Muscle Satellite Cells during Injury-Induced Muscle Regeneration.
Cell Reports. 2016 Aug 10. pii: S2211-1247(16)30959-7.
Liu L, Cheung TH, Charville GW, Hurgo BM, Leavitt T, Shih J, Brunet A, Rando TA.
Chromatin Modifications as determinants of muscle stem cell quiescence and chronological aging.
Cell Reports. 2013 Jun 27. doi:pii: S2211-1247(13)00276-3. 10.1016/j.celrep.2013.05.043.
Cheung TH, Rando TA.
Molecular regulation of stem cell quiescence.
Nat Rev Mol Cell Biol. 2013 Jun;14(6):329-40. doi: 10.1038/nrm3591.
Cheung TH, Quach NL, Charville GW, Liu L, Park L, Edalati A, Yoo B, Hoang P, Rando TA.
Maintenance of muscle stem-cell quiescence by microRNA-489.
Nature. 2012 Feb 23;482(7386):524-8. doi: 10.1038/nature10834.
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