A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state1. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function2. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an ‘alert’ phase we term GAlert. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into GAlert and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-GAlert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into GAlert possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into GAlert functions as an ‘alerting’ mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.
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We would like to thank members of the Rando laboratory for discussions critical to the preparation of this manuscript, especially T. Cheung and S. Biressi. We thank L. Rott for providing assistance with FACS. This work was supported by The Glenn Foundation for Medical Research, by a grant from the Department of Veterans Affairs to T.A.R., and grants from the National Institutes of Health to J.T.R. (K99 AG041764), K.Y.K (K08 HL098898), M.A.G. (R01 DK092883) and to T.A.R. (P01 AG036695, R01 AG23806 and R01 AR062185).
The authors declare no competing financial interests.
Extended data figures and tables
Extended Data Figure 1 SCs distant from the site of an injury display a functional response to the injury.
a, Representative FACS plot from isolation of EYFP+ SCs from 10-week-old Pax7CreER/+; Rosa26EYFP/+ mice 3 weeks following TMX treatment. Mononuclear cells from muscle digests were gated in FITC and Pac-Blue (autofluorescence) channels to separate EYFP+ SCs. EYFP+ SCs were usually 2–4% of all events from muscle digestions. b, Progeny of CSCs and QSCs take comparable times to complete the second cell division. Analysis of the time required to complete the second division (QSCs 10.2 ± 2 h, n = 148 cells; CSCs 10.9 ± 2 h, n = 155), following the first cell cycle (Fig. 1d), shows that accelerated cell cycle kinetics of CSCs is limited to the first division. c, SCs throughout the body increase in propensity to cycle in response to injury. In injured animals, SCs isolated from indicated muscle groups show higher frequency of BrdU incorporation when compared to SCs from the same muscle groups from non-injured mice (n ≥ 2 animals). d, Muscle crush injuries increase the in vivo cycling propensity of CSCs. Twelve hours after BrdU pulse labelling, SCs isolated from TA and Gast muscles contralateral to muscle crush injury show elevated BrdU labelling frequency versus SCs from those muscles from non-injured mice (mean ± s.e.m.; non-injured, n = 5 animals; muscle crush, n = 3; **P < 0.01). e, SCs contralateral to a muscle crush injury have increased cell cycle entry kinetics. 2.5 DPI SCs contralateral to a muscle crush injury incorporate EdU more rapidly than QSCs when cultured ex vivo for 40 h (mean ± s.e.m., n = 3 animals, *P < 0.05).
a, CSCs are slightly larger than QSCs and much smaller than ASCs. Immediately after isolation, analysis of cell diameters of QSCs, 2.5 DPI CSCs and 2.5 DPI ASCs, measured by phase contrast microscopy, shows that CSCs have a distribution that is shifted to the right compared to QSCs (histographic representation of data displayed in Fig. 2a, b). b, CSCs are larger than QSCs as measured by the FSC parameter by FACS (representative FACs plot, similar results observed in 4 independent experiments). c, CSCs have elevated intensity of an EYFP reporter. FACS analysis of EYFP intensity in the FITC channel shows that 2.5 DPI CSCs display a slight shift in EYFP distribution relative to QSCs, suggesting increased expression of this reporter from the Rosa26 locus (representative FACS plot, similar results observed in 4 independent experiments). d, CSCs show elevated levels of pyronin Y staining, suggesting an increased RNA content relative to QSCs, but substantially less than ASCs (representative FACS plot, similar results observed in 4 independent experiments). e, CSCs increase global transcriptional activity compared with QSCs. FACS analysis of EU incorporation, following pulse labelling by i.p. injection, shows that 2.5 DPI CSCs have higher levels of EU nucleotide incorporation than QSCs, whereas ASCs show markedly elevated incorporation. f–i, Immunocytochemical (ICC) staining of QSCs, 2.5 DPI CSCs and 2.5 DPI ASCs immediately after isolation shows that CSCs are highly similar to QSCs in expression of the QSC marker Pax7 (f), as well as markers of SC activation, MyoD (g) and Ki67 (h), and myogenic differentiation, MyoG (i) (mean ± s.e.m.; n = 4 animals; *P < 0.05, **P < 0.01). j, CSCs have comparable ability to engraft as QSCs. EYFP+ QSCs and 2.5 DPI CSCs were isolated from donor mice (Pax7CreER/+; Rosa26EYFP/+). A total of 5 × 104 EYFP+ QSCs were transplanted into the left TAs and 5 × 104 EYFP+ CSCs were transplanted into the right TAs of host NSG mice. Two weeks after transplantation, EYFP+ SCs were isolated from TA muscles of host mice and SC engraftment efficiency was measured as the number of EYFP+ SCs that were recovered as a percentage of the number of donor SCs that were transplanted (n = 4, red line indicates mean). For both donor cell populations, greater than 95% of SCs recovered were found to be Pax7+ as measured by ICC (data not shown). k, CSCs that incorporate BrdU self-renew. Following injury to one TA muscle, mice were administered BrdU continuously for 4 days followed by 21 days of chase (as shown in the diagram). IF-IHC analysis of the TA contralateral to the injury revealed BrdU+ Pax7+ cells in the satellite cell position beneath the basal lamina. An example of such a cell is illustrated here (top row of images). On the right is quantification of BrdU+ SCs after 21 days of chase by ICC after FACS isolation, showing that CSCs have self-renewal capacity similar to QSCs (mean ± s.e.m., n = 3 animals, *P < 0.05). Below is an example of a BrdU+ myonucleus in the contralateral TA after 21 days of chase, suggesting that CSCs can also fuse with the adjacent fibre following proliferation.
a, Induction of genes involved in the cell cycle and mitochondrial metabolism in CSCs. Pathway analysis of genes that were induced in CSCs versus QSCs showed enrichment of genes involved in the cell cycle and mitochondrial metabolism. Redundant KEGG pathways that contain overlapping genes were assembled into annotation groups (details of array and enrichment analysis are found in the Methods section). b, CSCs have slightly increased cell volume compared to QSCs. Cell volume was calculated from cell size measurements (Fig. 2b) (mean ± s.e.m., n = 4 animals, *P < 0.05, **P < 0.01 compared to QSCs). c, CSCs have a slightly greater intracellular ATP concentration than QSCs (mean ± s.e.m., n = 4 animals, *P < 0.05 compared to QSCs). d, Increase in photo emission from CSCs expressing luciferase reporter (LuSEAP). Immediately after isolation and plating, bioluminescence imaging of 1 × 104 Pax7CreER/+; Rosa26LuSeAP/+ SCs shows that 2.5 DPI CSCs have greater luminescence than QSCs, ASCs have substantially elevated luminescence. Activated fibro-adipogenic progenitors (AFAPs) were isolated from the same injured muscle as ASCs and plated as a negative control for LuSEAP expression. Light emission from luciferase is dependent on the amounts of luciferase enzyme, ATP and luciferin. Increased ATP and increased expression from the Rosa26 locus in CSCs (Fig. 2j and Extended Data Fig. 2c) could both contribute to increased luminescence. Data presented are from a representative experiment with similar results observed in two independent experiments. e, Low magnification image of IF-IHC staining of TA muscle. Boxed areas are of the representative pS6− and pS6+ SCs that are shown in Fig. 2g. f, CSCs have increased levels of pS6 as shown by western blot analysis of whole-cell extracts from 1 × 105 cells of each population collected immediately after isolation. g, CSCs show a bimodal distribution of pS6 staining at 1 DPI, with peaks corresponding to the signal in pS6− QSCs and pS6+ ASCs when analysed by FACS (representative FACS plot, similar results observed in 3 independent experiments). h, Sorting SCs for properties of the alert state (that is, high levels of MitoTracker Deep Red (MTDR) staining and YFP expression) enriches for SCs that display the other properties of alert SCs: elevated mTORC1 activity, reduced time to first division and increased propensity to cycle. Representative gating of MTDRHi;EYFPHi SCs (Hi) and MTDRLo;EYFPLo SCs (Lo). i–m, Sorting of Hi SCs reveals a sub-population of QSCs that displays characteristics of the alert state. Hi SC cells have increased mTORC1 activity (i), an increased propensity to cycle in vivo as measured by incorporation of EdU nucleotide 12 h after pulse labelling (j), and an accelerated time to first division (k). Both Hi and Lo SCs stain positive for the SC marker, Pax7 (l). 12 h after an in vivo EdU pulse, most SCs that incorporate nucleotide (quantified in j) stain positive for pS6 (m). Panels i–m are displayed as mean ± s.e.m., n ≥ 3 animals, *P < 0.05, **P < 0.01.
a, TSC1 KO increases SC pS6 levels. IF-IHC staining shows no pS6 staining of SCs in wild-type TA muscle and strong staining of SCs in TSC1 KO TA (representative images of low-magnification muscle section, numbered boxed regions are shown in high magnification below). b, Levels of pS6 in SC-specific KO models. TSC1 KO SCs show induction of pS6 when compared to wild-type QSCs, whereas Rptor KO QSCs and CSCs show no detectable pS6. cMet KO QSCs show comparable levels of pS6 as wild-type QSCs. However, unlike wild-type CSCs, cMet KO CSCs show no induction of pS6. Displayed is western blotting analysis of whole cell extracts from 1 × 105 cells per each population/genetic model collected immediately after isolation. The first three lanes (WT: QSCs, CSCS and ASCs) are the same as Extended Data Fig. 3f and are redisplayed for the purpose of comparison. c, TSC1 KO SCs are larger than wild-type SCs (representative FACS plot, similar results observed in 4 independent experiments).
Extended Data Figure 5 Rptor and cMet KO SCs contralateral to injury display no ‘alerting’ response.
a, Depletion of Rptor protein in Rptor KO SCs. ICC staining of EYFP+ SCs cultured for 40 h after isolation shows that Rptor protein is undetectable in Rptor KO SCs but clearly detectable in wild-type SCs. b, Absence of pS6 in Rptor KO SCs. ICC staining shows that after 40 h in culture, EYFP+ wild-type SCs stain strongly pS6+ whereas EYFP+ Rptor KO SCs do not exhibit any detectable pS6 signal. c, PCR verification of Rptor exon 6 excision in Rptor KO SCs. Using primers flanking the floxed exon 6 of the Rptor genomic locus, PCR analysis of genomic DNA from SCs isolated from a Rptor conditional KO animal (Rptorfl/fl;Pax7CreER/+;Rosa26EYFP/+) shows efficient recombination of the floxed allele, whereas analysis of genomic DNA from SCs from a wild-type animal (Rptor+/+;Pax7CreER/+;Rosa26EYFP/+) and FAPs from a Rptor conditional KO animal does not show recombination. d, FACS analysis reveals that Rptor KO SCs are slightly smaller and display a slight leftward shift in FSC distribution relative to wild-type SCs. e, Rptor KO SCs do not enlarge in response to contralateral injury. 2.5 DPI, Rptor KO CSCs show a nearly identical FSC distribution to that of Rptor KO QSCs and do not increase in size in response to contralateral injury as do wild-type CSCs (d). a–e, Representative data, similar results observed in at least 3 independent experiments. f, cMet is required for phosphorylation of S6 by HGF. In culture, wild-type SCs show a robust increase in the frequency of pS6+ SCs in response to a 1 h stimulation with HGF whereas cMet KO SCs show no change in pS6 staining frequency (mean ± s.e.m., n = 4, **P < 0.01). g, cMet KO prevents induction of pS6 in SCs contralateral to injury as measured by IF-IHC (mean ± s.e.m.; n ≥ 3 animals, ≥ 50 Pax7+ SCs analysed from each animal; *P < 0.05). h, cMet KO CSCs do not change in size. FACS analysis shows that cMet KO and wild-type QSCs have similar FSC distributions and that this distribution is not altered in cMet KO SCs contralateral to an injury (a representative FACS plot is shown; similar results were observed in 3 independent experiments).
a, Frequency of pS6+ CSCs returns to non-injured levels 28 DPI. Quantification of the percentage of pS6+ SCs by IF-IHC shows that immediately following injury, most CSCs (orange bars) become pS6+. The frequency of pS6+ CSCs decreases to levels observed in non-injured animals (black bar) by 28 DPI (mean ± s.e.m., n ≥ 3 animals, > 50 Pax7+ SCs analysed from each animal, **P < 0.01 versus non-injured). b, The propensity of CSCs to cycle returns to the level of QSCs several weeks after injury. At various times after injury, mice were given an i.p. injection of BrdU. SCs were isolated 12 h later from the injured muscles (ASCs) or from the contralateral muscles (CSCs). The frequency of BrdU incorporation returned to QSC levels (dashed line) by approximately 21 days after injury for both ASCs and CSCs (mean ± s.e.m.; n ≥ 3 animals). c, Cell cycle entry kinetics of CSCs returns to the level of QSCs several weeks after injury. At various times after injury, SCs or their progeny were isolated from the injured muscles (ASCs) or from the contralateral muscles (CSCs) and cultured in vitro for 40 h in the presence of EdU. The frequency of EdU incorporation returned to QSC levels (dashed line) by several weeks after injury for both ASCs and CSCs (mean ± s.e.m., n ≥ 2 animals). d, CSCs isolated 28 DPI have a transcriptional profile very similar to QSCs as shown by PCA and Pearson’s r value. Transcriptome analysis was performed as in Fig. 2c, with the addition of data from CSCs 28 DPI.
Extended Data Figure 7 The ability to adopt the alert state strongly correlates with expression of genes involved in mitochondrial metabolism.
a, Pathway analysis (as performed in Extended Data Fig. 3a) of the genes induced in TSC1 KO QSCs compared to wild-type QSCs shows that genes involved in mitochondrial metabolism are significantly enriched. b, c, Pathway analyses of the genes induced in Rptor KO CSCs compared to Rptor KO QSCs (b) and cMet KO CSCs compared to cMet KO QSCs (c) show that genes involved in mitochondrial metabolism are not enriched. d, Expression of genes involved in oxidative phosphorylation (KEGG ID mmu00190) is coupled with the alert state. Heat map of the expression of genes in the oxidative phosphorylation pathway shows that models of the alert state (CSCs and TSC1 KO QSCs) have elevated expression of these genes and that models of non-alert SCs (QSCs, Rptor KO SCs and cMet KO SCs) have low expression of these genes. Hierarchical clustering (Euclidean distance, complete linkage) shows that models of the alert state (CSCs and TSC1 KO SCs) cluster together and that models of non-alert SCs (QSCs, Rptor KO SCs and cMet KO SCs) form another cluster. e, Centroid-based clustering using oxidative phosphorylation genes (KEGG ID mmu00190) shows that grouping SCs into three clusters reveals an ‘alert’ cluster (wild-type CSCs and TSC1 KO QSCs), a ‘non-alert’ cluster (QSCs, CSCs 28 DPI, Rptor KO QSCs and CSCs and cMet KO QSCs and CSCs), and an ‘activated’ cluster (ASCs). Ellipses of dispersion show standard deviation (radius) and mean (centre) for each cluster using the first two components from PCA. Combined, these data show that induction of genes involved in mitochondrial metabolism strongly and consistently correlates with ability to adopt the alert state: wild-type CSCs and TSC1 KO QSCs are alert, and Rptor KO and cMet KO CSCs are not alert.
a, Cultures of CSCs differentiate more quickly than do cultures of QSCs (representative ICC staining of MyoG, data quantified in Fig. 4a, b). b, SCs enter the alert state in response to injuries to non-muscle tissue. SCs contralateral to a tibial fracture (bone inj) and SCs in an animal that received a skin wound on the abdomen (skin inj) increase in propensity to cycle in vivo (mean ± s.e.m.; non-injured, n = 5 animals; bone injured, n = 2; skin injured, n = 6; **P < 0.01 versus non-injured). c, SCs increase cycle cell entry kinetics in response to non-muscle injuries. SCs contralateral to a tibial fracture injury and SCs from mice that received a skin injury have increased frequency of EdU incorporation when cultured for 40 h ex vivo compared to SCs from non-injured animals (mean ± s.e.m.; n = 3 animals; *P < 0.05 versus non-injured).
a, Increased frequency of pS6+ FAPs contralateral to muscle injury. Representative IF-IHC staining of TA muscle from a non-injured animal (top) or contralateral to injury (bottom) shows that the frequency of pS6+ (PDGFRα+;CD31−) FAPs is increased in contralateral muscle (data are quantified in Fig. 4g). Labelled boxes indicate regions for which higher magnification is displayed. b, CFAPs increase in size. FACS analysis shows that 2.5 DPI CFAPs increase in FSC distribution compared to QFAPs; AFAPs show a greater increase in size (a representative FACs plot is shown, similar results were observed in 3 independent experiments). c, CFAPs increase in propensity to cycle. Twelve hours following an i.p. injection of BrdU, CFAPs isolated at indicated DPIs have an elevated frequency of BrdU incorporation compared to QFAPs (0 DPI). d, Muscle injury increases the frequency of phospho-mTOR+ (pmTOR) LT-HSCs. FACS analysis of pmTOR in Lineage−, Sca-1+, cKit+, CD150+ HSCs isolated from bone marrow 1 DPI showed that LT-HSCs induce mTORC1 signalling in response to muscle injury (mean ± s.e.m.; n ≥ 4; *P < 0.05).
This file contains the microarray data for WT QSCs, WT CSCs 2.5 DPI, WT CSCs 28 DPI, WT ASCs 2.5 DPI, TSC1 KO QSCs, Rptr KO QSCs, Rptr KO CSCs 2.5 DPI, cMet KO QSCs, cMet KO CSCs 2.5 DPI. Details on microarray data processing and filtering are described in the Supplemental Methods section. (XLSX 18229 kb)
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Rodgers, J., King, K., Brett, J. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert. Nature 510, 393–396 (2014). https://doi.org/10.1038/nature13255
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