Stem Cells on Alert: Priming Quiescent Stem Cells after Remote Injury
2014; Elsevier BV; Volume: 15; Issue: 1 Linguagem: Inglês
10.1016/j.stem.2014.06.012
ISSN1934-5909
Autores Tópico(s)Planarian Biology and Electrostimulation
ResumoA recent paper published by Rodgers et al. describes a novel phase of stem cell quiescence, termed GAlert, that serves to prime cells in response to injury-induced signals. These stem cells are located distal to the site of injury and require mTORC1 activity to elicit the alert response. A recent paper published by Rodgers et al. describes a novel phase of stem cell quiescence, termed GAlert, that serves to prime cells in response to injury-induced signals. These stem cells are located distal to the site of injury and require mTORC1 activity to elicit the alert response. Adult stem cells possess the unique ability to remain quiescent for long periods of time. When triggered by tissue loss or injury, these stem cells rapidly exit their dormant state, known as G0, and become activated to enter the G1 phase of the cell cycle. Stem cell fate is determined in G1, whereby differentiated daughter cells can be generated or a return to quiescence can be achieved (Cheung and Rando, 2013Cheung T.H. Rando T.A. Nat. Rev. Mol. Cell Biol. 2013; 14: 329-340Crossref PubMed Scopus (712) Google Scholar).The ability of stem cells to transition from a quiescent, G0 state to an actively cycling state is paramount to their regenerative capacity, and an imbalance in these two states can have pathologic consequences (Rossi et al., 2012Rossi L. Lin K.K. Boles N.C. Yang L. King K.Y. Jeong M. Mayle A. Goodell M.A. Cell Stem Cell. 2012; 11: 302-317Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). In a recent paper published in Nature, Rodgers and colleagues describe the existence of a novel, functional phase of quiescence, termed "GAlert" (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar). They demonstrate that upon induction of muscle injury in a single limb of a mouse, muscle stem cells (satellite cells) from the contralateral uninjured limb muscle show a higher propensity to enter the cell cycle when compared to quiescent satellite cells without actually proceeding to an activation stage (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar). Thus, they propose that stem cell quiescence is actually composed of two distinct phases, G0 and GAlert, and that stem cells can reversibly transition to GAlert in response to injury in order to be primed for activation and entry into the cell cycle (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar). Through a rigorous set of studies, the authors characterize GAlert as an intermediate state between quiescence and activation. GAlert cells are slightly larger in size and they are able to enter and complete the cell cycle faster than quiescent satellite cells (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar). Furthermore, GAlert cells have higher intracellular ATP content and greater mitochondrial activity when compared to quiescent satellite cells (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar) (Figure 1). These parameters clearly demonstrate that GAlert satellite cells fall between the two traditional stem cell states with a tendency to be more similar to quiescent cells. Until recently, the regulation of quiescence was poorly characterized and it was presumed that quiescence was simply a state of dormancy with little cellular activity. The transcriptomes of three distinct stem cell types, hematopoietic, muscle, and hair follicle stem cells, in G0 compared to actively cycling stem cells demonstrates downregulation of genes involved in cell cycle progression including cyclins A2, B1, and E2 and mitochondrial biogenesis genes such as cytochrome C. Upregulated genes include those involved in stem cell fate determination such as forkhead box O3 (FOXO3) and enhancer of zeste homology 1 (EZH1) (Cheung and Rando, 2013Cheung T.H. Rando T.A. Nat. Rev. Mol. Cell Biol. 2013; 14: 329-340Crossref PubMed Scopus (712) Google Scholar). In contrast, transcriptome analyses conducted by Rodgers et al. demonstrate that genes specifically involved in cell cycle regulation and mitochondrial metabolism are significantly upregulated in contralateral satellite cells despite such cells maintaining a state of quiescence and not entering the active cell cycle (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar). This unique transcriptional profile of contralateral satellite cells further supports their model describing a distinct population of stem cells that exist in an intermediate state between quiescence and activation. To address the functional significance of the primed state of GAlert satellite cells, Rodgers et al. demonstrated that GAlert cells exhibit enhanced muscle regenerative capacity in vivo after injury. Interestingly, the GAlert response in satellite cells was not specific to muscle injury because a similar activation response was observed after injury to bone and skin. In addition, the GAlert response after muscle injury is not restricted to satellite cells, because fibro-adipogenic progenitors and hematopoietic stem cells also demonstrated a primed phenotype accompanied by a more robust functional response. These findings are of particular interest because they suggest that the primed stem cell status observed in satellite cells may not be unique to muscle. Future studies will need to address whether other injured tissues elicit similar responses. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that interacts with several proteins to form one of two large complexes: mTOR complex 1 (mTORC1) or mTORC2. mTORC1 signaling predominantly regulates growth and cell cycle progression and is sensitive to diverse environmental stimuli including stress and fluctuations in nutrient availability. Several of these stimuli transmit their signals through tuberous sclerosis proteins 1 and 2 (TSC1/2) that negatively regulate mTORC1 activity (Laplante and Sabatini, 2012Laplante M. Sabatini D.M. Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (6136) Google Scholar). Increased mTORC1 signaling has been shown to activate hematopoietic stem cell cycling (Gan et al., 2008Gan B. Sahin E. Jiang S. Sanchez-Aguilera A. Scott K.L. Chin L. Williams D.A. Kwiatkowski D.J. DePinho R.A. Proc. Natl. Acad. Sci. USA. 2008; 105: 19384-19389Crossref PubMed Scopus (174) Google Scholar) and induces the differentiation of activated neural stem cells (Hartman et al., 2013Hartman N.W. Lin T.V. Zhang L. Paquelet G.E. Feliciano D.M. Bordey A. Cell Rep. 2013; 5: 433-444Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Because mTORC1 signaling is a known regulator of cell cycle progression in diverse stem cell populations, the authors confirmed active mTORC1 signaling in GAlert satellite cells and investigated whether modulating this signaling could regulate the GAlert response. The authors utilized the Pax7CreER driver to ablate components of mTORC1 signaling specifically in satellite cells. Upon TSC1 ablation that induces increased mTORC1 activity, they found quiescent satellite cells in the GAlert state without any contralateral injury. Conversely, satellite-cell-specific ablation of Raptor, a member of mTORC1, caused suppressed mTORC1 signaling in satellite cells accompanied by a complete lack of the GAlert phenotype in contralateral satellite cells after injury. Finally, the authors targeted an upstream activator of mTORC1 signaling, latent hepatocyte growth factor (HGF), which normally resides in the extracellular matrix and is activated upon injury. Once active, HGF signals via its receptor, cMet, to regulate mTORC1 signaling. cMet knockout blocked mTORC1 signaling and failed to generate an alert response in contralateral satellite cells after injury. Taken together, these results demonstrate that mTORC1 activity is both necessary and sufficient for quiescent satellite cells to enter the alert phenotype. However, the mechanism by which mTORC1 signaling is activated in a population of stem cells resident in muscle distal to the site of injury remains unknown. One possibility is the release or induction of a circulating factor that serves as an activator of mTORC1 at sites distal to the site of injury (Figure 1); the priming of hematopoietic stem cells after muscle injury would support this hypothesis. The current findings of a generalized "alerting response" to injury that is tightly regulated by mTORC1 signaling may also shed some light into previously published data related to rapamycin (an inhibitor of mTOR signaling) and aging. In 2009, Harrison et al., 2009Harrison D.E. Strong R. Sharp Z.D. Nelson J.F. Astle C.M. Flurkey K. Nadon N.L. Wilkinson J.E. Frenkel K. Carter C.S. et al.Nature. 2009; 460: 392-395Crossref PubMed Scopus (2695) Google Scholar reported that rapamycin increased both mean and maximum life span of mice, demonstrating that all competing causes of mortality (i.e., age-related diseases) are delayed and suggesting that rapamycin slows aging. In a subsequent study, Neff et al., 2013Neff F. Flores-Dominguez D. Ryan D.P. Horsch M. Schröder S. Adler T. Afonso L.C. Aguilar-Pimentel J.A. Becker L. Garrett L. et al.J. Clin. Invest. 2013; 123: 3272-3291Crossref PubMed Scopus (281) Google Scholar demonstrated that while rapamycin extended the overall life span of animals, it did not ameliorate a number of pathophysiological aging phenotypes. Given that a number of aging-related phenotypes are associated with an overall decreased regenerating capacity of certain tissues, the current study by Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; (in press. Published online May 25, 2014)https://doi.org/10.1038/nature13255Crossref Scopus (419) Google Scholar may explain this at least to some degree.
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