Molecular regulation of stem cell quiescence

Cheung, Tom H.; Rando, Thomas A.

doi:10.1038/nrm3591

Cited by 935 publications

(915 citation statements)

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“…In adult tissues, satellite cells are kept in a quiescent state until they are activated to regenerate damaged muscle through cycles of self‐renewal divisions (reviewed in (Montarras, L'Honoré, & Buckingham, 2013)). The ability of satellite cells to repair injured muscle markedly declines with aging (Cheung & Rando, 2013). Aside from reduced numbers of satellite cells (Garcia‐Prat, Sousa‐Victor, & Munoz‐Canoves, 2013; Shefer, Mark, Richardson, & Yablonka‐Reuveni, 2006), the differentiation capacity of satellite cells is also reduced with aging.…”

Section: Introduction Results Discussionmentioning

confidence: 99%

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

et al. 2018

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Tissue regeneration is a highly coordinated process with sequential events including immune cell infiltration, clearance of damaged tissues, and immune‐supported regrowth of the tissue. Aging has a well‐documented negative impact on this process globally; however, whether changes in immune cells per se are contributing to the decline in the body’s ability to regenerate tissues with aging is not clearly understood. Here, we set out to characterize the dynamics of macrophage infiltration and their functional contribution to muscle regeneration by comparing young and aged animals upon acute sterile injury. Injured muscle of old mice showed markedly elevated number of macrophages, with a predominance for Ly6Chigh pro‐inflammatory macrophages and a lower ratio of the Ly6Clow repair macrophages. Of interest, a recently identified repair macrophage‐derived cytokine, growth differentiation factor 3 (GDF3), was markedly downregulated in injured muscle of old relative to young mice. Supplementation of recombinant GDF3 in aged mice ameliorated the inefficient regenerative response. Together, these results uncover a deficiency in the quantity and quality of infiltrating macrophages during aging and suggest that in vivo administration of GDF3 could be an effective therapeutic approach.

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Section: Introduction Results Discussionmentioning

confidence: 99%

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

et al. 2018

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“…Quiescence is involved in important cellular processes, including the balance between differentiation and self-renewal in different types of stem cells, and dysregulation of quiescence could favor carcinogenesis. However, the molecular mechanisms that regulate quiescence are poorly understood (6). miRNAs are small, noncoding RNAs ∼22-nt long that regulate the expression of protein-coding genes by base-pairing with the 3′ UTR of mRNAs, repressing the translation and/or inducing the degradation of the target mRNA (7,8).…”

mentioning

confidence: 99%

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

Martínez

Hayes

Barr

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The reversible state of proliferative arrest known as "cellular quiescence" plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNAprocessing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.M ost metazoan cells enter a reversible cell-cycle arrest known as "cellular quiescence" when they are exposed to antimitogenic signals or an environment unfavorable for proliferation (1, 2). In mammalian cells, quiescence (also known as "G 0 arrest") is characterized by reduced DNA replication, altered metabolism, increased autophagy, and increased expression of cyclin-dependent kinase inhibitors such as p27 Kip1 (3,4). In vitro, quiescence can be induced in primary cells by serum starvation, contact inhibition, and loss of adhesion to a substrate (5). Quiescence is involved in important cellular processes, including the balance between differentiation and self-renewal in different types of stem cells, and dysregulation of quiescence could favor carcinogenesis. However, the molecular mechanisms that regulate quiescence are poorly understood (6). miRNAs are small, noncoding RNAs ∼22-nt long that regulate the expression of protein-coding genes by base-pairing with the 3′ UTR of mRNAs, repressing the translation and/or inducing the degradation of the target mRNA (7,8). In canonical miRNA biogenesis in mammalian cells, miRNAs are transcribed by RNA polymerase II to produce 7-methylguanosine (m 7 G)-capped primary miRNAs (pri-miRNAs) containing one or more bulged hairpin structures that are recognized by the nuclear microprocessor, which consists of the RNase III enzyme Drosha and the dsRNA-binding protein DGCR8 (DiGeorge syndrome critical region gene 8) (9-12). Specific cleavage of the pri-miRNA by the nuclear microprocessor generates an ∼70-nt stem-loop structure known as the "precursor miRNA" (pre-miRNA), which is recognized and transported to the cytoplasm by 10,11,13). Subsequently, pre-miRNA is cleaved by the cytoplasmic RNase III enzyme Dicer (14-17), generating a double-stranded mature mi...

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“…15 However, external stimuli in the form of injury may suppress tissue-specific miRNAs, which in turn may lead to alterations in adult resident SCs such that they start to differentiate, akin to their embryonic counterpart, with the objective to enact tissue repair. This is one example of how regeneration is largely inspired by mechanistic underpinning of embryo development.…”

Section: Development Is the Key To Regenerationmentioning

confidence: 99%