CoChat
Sign Up
Cited by 1,148Hematopoietic Stem Cell TransplantationDevelopmental Biology and Gene RegulationMesenchymal stem cell research

Molecular regulation of stem cell quiescence

Open access
Cheung, Tom H., Rando, Thomas A.·2013·Nature Reviews Molecular Cell Biology
DOI 10.1038/nrm3591PMC PMC3808888
Open this paper in CoChat — free account

Abstract

Subsets of mammalian adult stem cells reside in the quiescent state for prolonged periods of time. This state, which is reversible, has long been viewed as dormant and with minimal basal activity. Recent advances in adult stem cell isolation have provided insights into the epigenetic, transcriptional and post-transcriptional control of quiescence and suggest that quiescence is an actively maintained state in which signalling pathways are involved in maintaining a poised state that allows rapid activation. Deciphering the molecular mechanisms regulating adult stem cell quiescence will increase our understanding of tissue regeneration mechanisms and how they are dysregulated in pathological conditions and in ageing.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that adult stem cell quiescence is not passive dormancy but an actively maintained, reversible condition primed for rapid activation. It synthesizes transcriptional, epigenetic, post-transcriptional, signalling, metabolic, and genome-protective mechanisms across several tissue stem cell populations.

Key findings

  • Quiescent stem cells share a transcriptional signature: downregulation of DNA replication and cell-cycle genes such as cyclin A2, cyclin B1, cyclin E2, survivin, PCNA, and MCM4, plus reduced mitochondrial CYCS; upregulation of regulators including FOXO3 and EZH1, based on comparisons of haematopoietic, muscle, and hair follicle stem cells.
  • Quiescence is enforced by p53/RB, CDK inhibitors (p21, p27, p57), Notch signalling in muscle and neural stem cells but not haematopoietic stem cells, and microRNAs such as miR-126 in haematopoietic stem cells and miR-489/miR-31 in muscle stem cells; disrupting these pathways causes premature activation, differentiation, or stem cell pool exhaustion.
  • Survival during quiescence involves FOXO-mediated resistance to oxidative stress, HIF1α and LKB1 metabolic sensing, autophagy through Atg7, and DNA repair; quiescent haematopoietic stem cells preferentially use error-prone non-homologous end-joining, which may permit mutation accumulation.
  • The authors propose that quiescence is a poised condition: permissive H3K4me3 marks, miRNA-mediated fine-tuning, and 3′ UTR regulation keep activation programmes ready while limiting energy expenditure.

Methods

  • Design: narrative review, not a primary experimental study; it synthesizes published literature and advances a conceptual model.
  • Data or sample: cited studies of adult stem cell populations including haematopoietic, muscle, neural, hair follicle, and intestinal stem cells; no new sample, dataset, or original quantitative results are reported.
  • Analysis: conceptual integration of genetic ablation, lineage tracing, transcriptomic, epigenetic, and post-transcriptional findings; no formal meta-analysis or statistical method is described.

Limitations

  • The paper states that the molecular control of quiescence remains incompletely understood and that some epigenetic correlations and their significance still require experimental demonstration.
  • It identifies unresolved issues: mechanisms of asymmetric chromosome segregation remain undetermined, its prevalence varies by experimental paradigm, and Notch’s role in quiescence in some compartments remains to be determined.
  • Evident from the text: as a review, it provides no primary data, systematic search strategy, or quantitative synthesis, so its conclusions depend on cited studies and the authors’ proposed model.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrm3591

Cites

164 of 164 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 171 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Many H3K4me3-rich genes in quiescent HFSCs or MuSCs are expressed at low levels.

    “In support of the hypothesis that the quiescent state is poised for activation, many of these H3K4me3-rich genes (most of which are expressed at low levels) are functionally important for activation and proliferation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Lien, W.-H. et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219–232 (2011). source

      Not checked in the free run.

    • cites [62] Woodhouse, S., Pugazhendhi, D., Brien, P. & Pell, J. M. Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation. J. Cell. Sci. 126, 565–579 (2013). source

      Not checked in the free run.

  • Findingown data

    Many H3K4me3-rich genes in quiescent HFSCs or MuSCs are functionally important for activation and proliferation.

    “In support of the hypothesis that the quiescent state is poised for activation, many of these H3K4me3-rich genes (most of which are expressed at low levels) are functionally important for activation and proliferation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Lien, W.-H. et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219–232 (2011). source

      Not checked in the free run.

    • cites [62] Woodhouse, S., Pugazhendhi, D., Brien, P. & Pell, J. M. Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation. J. Cell. Sci. 126, 565–579 (2013). source

      Not checked in the free run.

  • Findingown data

    Epigenetic profiling of the H3K4me3 mark in quiescent HFSCs or quiescent MuSCs has revealed a number of genes marked by this permissive histone mark.

    “Epigenetic profiling of the H3K4me3 mark in quiescent HFSCs or quiescent MuSCs (T.H.C and T.A.R, unpublished observations) has revealed a number of genes that are marked by this permissive histone mark61,62.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Lien, W.-H. et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219–232 (2011). source

      Not checked in the free run.

    • cites [62] Woodhouse, S., Pugazhendhi, D., Brien, P. & Pell, J. M. Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation. J. Cell. Sci. 126, 565–579 (2013). source

      Not checked in the free run.

  • Interpretationnone given

    Label retention alone is insufficient to identify adult stem cells.

    “However, it has become increasingly apparent that the use of label retention alone is insufficient to identify adult stem cells.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Loss or dysregulation of quiescence often causes an imbalance in progenitor populations and eventually depletes stem cells.

    “dysregulation and loss of quiescence often results in an imbalance in progenitor cell populations ultimately leading to stem cell depletion3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Orford, K. W. & Scadden, D. T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nature Rev. Genet. 9, 115–128 (2008). source

      Not checked in the free run.

  • May combine two claims. 40
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    In somatic tissues, some cells divide continuously while others are non-proliferative during homeostasis but can re-enter the cell cycle after extrinsic stimuli.

    “In somatic tissues, some cells continuously divide, while other cells exist in a non-proliferative state during homeostasis but are able to respond to extrinsic stimuli and re-enter the cell cycle to begin proliferating5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Baserga, R. Biochemistry of the cell cycle: a review. Cell Prolifer. 1, 167–191 (1968). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Early studies suggested that a quiescent state exists and that access to it is restricted.

    “Together, these early studies suggested the existence of a quiescent state, access to which is restricted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pardee provided evidence for a distinct quiescent state and an R-point in G1 that determines cell fate.

    “In 1974, Pardee provided evidence for a distinct quiescent state and demonstrated the existence of a restriction point (R-point) in G1 that determines cell fates”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Pardee, A. B. A restriction point for control of normal animal cell proliferation. Proc. Natl Acad. Sci. USA 71, 1286–1290 (1974). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many unicellular organisms remain quiescent for prolonged periods to survive unfavourable environments.

    “Many unicellular organisms reside in the quiescent state for a prolonged period of time to survive in unfavourable environments11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Gray, J. V. et al. 'Sleeping beauty': quiescence in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 68, 187–206 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cells in G1 can become quiescent before the R-point but commit to mitosis after it.

    “cells in G1 can become quiescent before the R-point but commit to enter a mitotic cell cycle after the R-point9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Pardee, A. B. A restriction point for control of normal animal cell proliferation. Proc. Natl Acad. Sci. USA 71, 1286–1290 (1974). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Plants use seed dormancy to preserve growth capacity and circumvent unfavourable environments.

    “studies of seed dormancy revealed that plants utilize this state to preserve the capacity for growth, thereby circumventing an unfavourable environment12.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Amen, R. D. A model of seed dormancy. Bot. Rev. 34, 1–31 (1968). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the gut, active stem cells function during normal homeostasis, while quiescent label-retaining cells serve as a reserve pool called upon after injury.

    “Whereas active stem cells function during normal homeostasis, quiescent LRCs seem to serve as a reserve pool of stem cells, only called into action upon tissue injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Buczacki, S. J. A. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65–69 (2013). Describes a strategy to genetically mark quiescent crypt cells in the gut and provides a new method to document the behaviour of LRCs over time. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum deprivation inhibits protein synthesis in all cell cycle states, but only early G1 cells exit the cycle and become quiescent.

    “serum deprivation results in the inhibition of protein synthesis in all cell cycle states but that only cells in early G1 exit the cell cycle and become quiescent10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Zetterberg, A. & Larsson, O. Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. Proc. Natl Acad. Sci. USA 82, 5365–5369 (1985). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Not all H3K4me3-marked genes are actively transcribed in quiescent stem cells; the mark may identify genes transcribed upon activation.

    “it is likely that not all genes marked by H3K4me3 are indeed being actively transcribed but may reflect the fact that quiescent stem cells are, in general, less differentiated than their proliferating progeny and that this epigenetic mark identifies genes that may be transcribed upon activation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Quiescent stem cells are generally less differentiated than their proliferating progeny.

  • May combine two claims.

    Premisecitation

    Quiescent bulge stem cells participate in wound healing but not normal homeostasis.

    “quiescent stem cells in the bulge are involved in the process of wound healing but not normal homeostasis35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005). Shows that ablation of hair follicle stem cells in the bulge leads to complete loss of hair follicles but the survival of the epidermis, suggesting that quiescent hair follicle stem cells are only called into action during would repair but not during normal homeostasis of the epidermis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of EZH2 in muscle impairs MuSC proliferation and derepresses non-muscle lineage genes.

    “In muscle, deletion of EZH2 impairs MuSC proliferation and derepresses gene expressions of non-muscle lineages58.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Juan, A. H. et al. Polycomb EZH2 controls self-renewal and safeguards the transcriptional identity of skeletal muscle stem cells. Genes Dev. 25, 789–794 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    H3K4me3 and H3K27me3 positively and negatively regulate transcription, respectively.

    “Trimethylation of histone H3 at Lys4 (H3K4me3) and H3K27me3 are of particular interest because of their roles in the positive and negative regulation of transcription, respectively54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome. Cell 128, 669–681 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In ES cells, ablation of RB, p107, and p130 impairs differentiation and increases cell turnover under growth arrest.

    “In ES cells, ablation of all three RB family members (RB, p107 and p130) results in impaired differentiation and an increase in cell turnover under growth arrest conditions69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Dannenberg, J. H., van Rossum, A., Schuijff, L. & te Riele, H. Ablation of the retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev. 14, 3051–3064 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ablation of RB in quiescent MuSCs increases muscle stem and progenitor cells and accelerates cell cycle re-entry.

    “Genetic ablation of RB in quiescent MuSCs results in a vast increase of muscle stem and progenitor cells and an acceleration of cell cycle re-entry70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Hosoyama, T., Nishijo, K., Prajapati, S. I., Li, G. & Keller, C. Rb1 gene inactivation expands satellite cell and postnatal myoblast pools. J. Biol. Chem. 286, 19556–19564 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    H3K4me3 marks genes for transcriptional activation but does not necessarily predict active transcription.

    “it has previously been proposed that H3K4me3 marks genes for transcriptional activation but does not necessarily predict whether these genes are being actively transcribed63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSCs lacking cyclin A2 cannot proliferate in vitro, indicating cyclin A2 is essential for HSC proliferation.

    “HSCs that lack cyclin A2 are unable to proliferate in vitro, indicating the essential role of cyclin A2 in HSC proliferation48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Kalaszczynska, I. et al. Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. Cell 138, 352–365 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thousands of genes in quiescent HFSCs and MuSCs are marked by H3K4me3, suggesting a permissive chromatin state for transcription.

    “in both quiescent HFSCs and MuSCs, thousands of genes are marked by the H3K4me3 mark (which is associated with active transcription)61,62, suggesting a permissive chromatin state for transcription.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Lien, W.-H. et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219–232 (2011). source

      Not checked in the free run.

    • cites [62] Woodhouse, S., Pugazhendhi, D., Brien, P. & Pell, J. M. Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation. J. Cell. Sci. 126, 565–579 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    FOXO3 and EZH1 are upregulated in quiescent stem cells.

    “genes that are upregulated in quiescent stem cells include genes encoding signalling molecules involved in transcriptional regulation and stem cell fate decisions such as forkhead box O3 (FOXO3) and enhancer of zeste homolog 1 (EZH1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    p53 deficiency in HSCs promotes cell cycle entry and reduces quiescent HSC number.

    “p53 deficiency in HSCs promotes cell cycle entry with a reduction in the number of quiescent HSCs64.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Liu, Y. et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4, 37–48 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p21 is an important regulator of G1 cell cycle progression and has been shown to regulate HSC quiescence.

    “p21, which is an important regulator of cell cycle progression at G1 that has previously been shown to regulate HSC quiescence65.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000). This is one of the earliest papers to suggest stem cell quiescence is actively regulated. Shows, using p21-deficent mice that HSC proliferation increases and the proportion of quiescent HSCs decreases. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of p27 does not affect HSC number or self-renewal but increases the haematopoietic progenitor pool.

    “inhibition of p27 does not affect the number or self-renewal of HSCs, but increases the size of the haematopoietic progenitor pool73.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Cheng, T., Rodrigues, N., Dombkowski, D., Stier, S. & Scadden, D. T. Stem cell repopulation efficiency but not pool size is governed by p27kip1. Nature Med. 6, 1235–1240 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Notch signalling is involved in tissue maintenance and contributes to cell fate decisions during tissue regeneration.

    “Notch signalling is involved in tissue maintenance and contributes to cell fate decisions during tissue regeneration76,77.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Luo, D., Renault, V. M. & Rando, T. A. The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis. Semin. Cell Dev. Biol. 16, 612–622 (2005). source

      Not checked in the free run.

    • cites [77] Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSC depletion after RB family ablation is accompanied by expansion of early haematopoietic progenitors and impaired reconstitution in transplantation.

    “This HSC depletion is accompanied by an expansion of early haematopoietic progenitors and an impairment of the reconstitution potential in transplantation experiments71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Viatour, P. et al. Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family. Cell Stem Cell 3, 416–428 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of p21 in HSCs and NSCs increases stem cell proliferation and decreases the quiescent stem cell population.

    “inhibition of p21 results in an increase in stem cell proliferation and in a decrease in the quiescent stem cell population65,72.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000). This is one of the earliest papers to suggest stem cell quiescence is actively regulated. Shows, using p21-deficent mice that HSC proliferation increases and the proportion of quiescent HSCs decreases. source

      Not checked in the free run.

    • cites [72] Kippin, T. E. & Martens, D. J. & van der Kooy, D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev. 19, 756–767 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p57 deficiency has no effect on HSC quiescence, possibly due to functional overlap with other CKIs.

    “The fact that p57 deficiency has no effect on HSC quiescence might be due to the functional overlap with other CKIs74,75.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Matsumoto, A. et al. p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell 9, 262–271 (2011). source

      Not checked in the free run.

    • cites [75] Zou, P. et al. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 9, 247–261 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of miR-126 in HSCs impairs cell cycle entry and lowers haematopoietic contribution.

    “overexpression of miR-126 in HSCs impairs cell cycle entry, resulting in a lower haematopoietic contribu-tion88.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Lechman, E. R. et al. Attenuation of miR-126 activity expands HSC in vivo without exhaustion. Cell Stem Cell 11, 799–811 (2012). Suggests that the HSC pool size could be fine-tuned by altering the level of miR-126 in HSCs and shows that miR-126 regulates HSC activation by targeting the PI3K—AKT— glycogen synthase kinase 3β pathway. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p27 and p57 control nuclear transport of the HSC70-cyclin D1 complex and regulate HSC cell cycle entry.

    “p27 and p57 control nuclear transport of the HSC70–cyclin D1 complex and regulate the cell cycle entry of HSCs75.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Zou, P. et al. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 9, 247–261 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Many CKIs including p21, p27, and p57 are expressed in quiescent stem cells and promote cell cycle arrest by inhibiting CDKs.

    “Many CKIs, including p21, p27 and p57, are expressed in quiescent stem cells and promote cell cycle arrest by inhibiting CDKs (FIG. 1a).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miRNAs bind the 3' UTR of target mRNAs, causing cleavage or translational repression.

    “miRNAs bind to the 3′ untranslated region (3′ UTR) of target mRNAs, resulting in their cleavage or trans-lational repression87.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Bartel, D. P. microRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although DSBs are repaired in quiescent stem cells, mutations may accumulate due to error-prone repair.

    “this suggests that although DSBs are repaired in quiescent stem cells, mutations may accumulate in these cells as a consequence of using error-prone repair mechanisms”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Quiescent stem cells can suffer DNA damage during normal homeostatic turnover and depend on DNA repair mechanisms for survival.

    “quiescent stem cells can also be subjected to DNA damage during normal homeostatic turnover, and quiescent stem cells depend on DNA repair mechanisms for survival123.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Lombard, D. B. et al. DNA repair, genome stability, and aging. Cell 120, 497–512 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Asymmetric chromosome segregation does not occur universally in stem cell compartments, and prevalence may differ by experimental paradigm.

    “asymmetric chromosome segregation does not occur universally in stem cell compartments, and its prevalence may differ depending on the experimental paradigm.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [135] Kiel, M. J. et al. Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449, 238–242 (2007). source

      Not checked in the free run.

    • cites [136] Sotiropoulou, P. A., Candi, A. & Blanpain, C. The majority of multipotent epidermal stem cells do not protect their genome by asymmetrical chromosome segregation. Stem Cells 26, 2964–2973 (2008). source

      Not checked in the free run.

    • cites [137] Kuroki, T. & Murakami, Y. Random segregation of DNA strands in epidermal basal cells. Jpn J. Cancer Res. 80, 637–642 (1989). source

      Not checked in the free run.

    • cites [138] Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M. & Clevers, H. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J. 30, 1104–1109 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic ablation of LKB1 causes loss of HSC quiescence, increased progenitor proliferation, and eventual HSC depletion.

    “upon genetic ablation of LKB1, HSC quiescence is lost and is accompanied by an increase in progenitor cell proliferation and eventual depletion of HSCs118–120”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). source

      Not checked in the free run.

    • cites [119] Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010). source

      Not checked in the free run.

    • cites [120] Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    NHEJ is error-prone, while homologous recombination is high-fidelity.

    “Whereas NHEJ is an error-prone DNA repair mechanism, homologous recombination is a high-fidelity DSB repair mechanism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NHEJ does not require a template and is predominantly used in G1.

    “NHEJ does not require a template and is predominantly used in G1 phase of the cell cycle125.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Shrivastav, M., Haro, L. P. D. & Nickoloff, J. A. Regulation of DNA double-strand break repair pathway choice. Cell Res. 18, 134–147 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSCs in HIF1α-knockout mice cannot maintain quiescence and the mice exhibit HSC depletion.

    “HSCs in HIF1α-knockout mice are not able to maintain quiescence, and these mice exhibit HSC depletion116.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Takubo, K. et al. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Environmental stress may damage cellular constituents including DNA, which has been proposed to underlie ageing and limit lifespan.

    “Environmental stress may lead to damage of cellular constituents, including DNA, a process that has been proposed to underlie the ageing of cells and tissue and to limit lifespan104,105.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Kregel, K. C. & Zhang, H. J. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R18–R36 (2007). source

      Not checked in the free run.

    • cites [105] Rossi, D. J., Jamieson, C. H. M. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy is induced in HSCs with conditional Lkb1 ablation, implying it may act as a compensatory mechanism to rescue metabolic stress.

    “Autophagy is also induced in HSCs in which Lkb1 is conditionally ablated, which implies that autophagy may act as a compensatory mechanism to rescue the metabolic stress in these mutants118.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSCs depleted of FOXO1, FOXO3, and FOXO4 show increased ROS and propensity to exit quiescence.

    “HSCs depleted of FOXO1, FOXO3 and FOXO4 exhibit a marked increase in ROS and the propensity to exit from quiescence107”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of ubiquitin-mediated degradation of HIF1α over-stabilizes HIF1α and induces HSC quiescence.

    “Inhibition of ubiquitin-mediated degradation of HIF1α results in over-stabilization of HIF1α protein and induction of HSC quiescence116”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Takubo, K. et al. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of LKB1 on HSC quiescence is cell autonomous, as LKB1-deficient HSCs cannot rescue lethally irradiated mice.

    “The effect of LKB1 on HSC quiescence is cell autonomous, as shown by transplantation experiments in which LKB1-deficient HSCs are not able to rescue lethally irradiate d recipient mice118–120.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). source

      Not checked in the free run.

    • cites [119] Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010). source

      Not checked in the free run.

    • cites [120] Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conditional knockout of Atg7 in the haematopoietic system reduces stem and progenitor cells of multiple lineages and causes accumulation of aberrant mitochondria and ROS.

    “Conditional knockout of the essential autophagy gene Atg7 in the haematopoietic system results in a reduced number of stem and progenitor cells of multiple lineages and the accumulation of aberrant mitochondria and ROS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Phosphorylation of Ser5 of the Pol II CTD by TFIIH is required for transcription initiation.

    “Phosphorylation of Ser5 of the Pol II CTD by transcription factor IIH (TFIIH) is required for transcription initiation, whereas phosphorylation of Ser2 of the Pol II CTD, of DSIF (DRB sensitivity inducing factor) and of NELF (negative elongation factor) by pTEFb (positive transcription elongation factor) is needed for transcription elongation141–143.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [141] Wada, T. et al. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 12, 343–356 (1998). source

      Not checked in the free run.

    • cites [142] Yamaguchi, Y. et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97, 41–51 (1999). source

      Not checked in the free run.

    • cites [143] Marshall, N. F., Peng, J., Xie, Z. & Price, D. H. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J. Biol. Chem. 271, 27176–27183 (1996). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Mechanisms in ES cells that allow silent genes to be activated precisely and synchronously may also apply to regulation of adult stem cell activation from quiescence.

    “The existence of mechanisms in ES cells that allow silent genes to be activated in a precise and synchronous fashion may also be applicable to the regulation of adult stem cell activation from the quiescent state.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Loci needed for stem cell activation are possibly marked by permissive histone marks.

    “In view of the epigenetic control of stem cell quiescence, loci required for stem cell activation are possibly marked by permissive histone marks.”
    Quote in the paperNot a substantial claim
45 of 45

  • The paper relies on this without support.

    In mammals, the ability of tissue stem cells to remain quiescent is crucial for proper homeostasis and regeneration of many tissues.

    “In mammals, the ability of tissue stem cells to reside in the quiescent state is crucial for proper homeostasis and regeneration of many tissue types.”

  • The paper relies on this without support.

    Mitochondrial biogenesis is required for stem cell activation.

    “As mitochondrial biogenesis is required for stem cell activation, low expression of CYCS reflects low metabolic activity of the quiescent stem cell.”

  • The paper relies on this without support.

    Quiescent stem cells are generally less differentiated than their proliferating progeny.

    “quiescent stem cells are, in general, less differentiated than their proliferating progeny”

  • The paper relies on this without support.

    The molecular control of quiescence remains to be fully elucidated.

    “To date, the molecular control of quiescence still remains to be fully elucidated.”

  • The paper relies on this without support.

    Quiescent stem cells are rare in many tissue compartments.

    “Our understanding of the characteristics of quiescent stem cells has been limited by the rarity of this population in many tissue compartments.”

  • The paper relies on this without support.

    Quiescent stem cells have a low metabolic state.

    “given the low metabolic state of a quiescent stem cell”
    “compatible with the low metabolic state of quiescence”

  • The paper relies on this without support.

    miRNAs can affect multiple target genes that are important in a shared pathway.

    “As miRNAs can affect a number of target genes that are important in a shared pathway”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • During adulthood, MuSCs remain mitotically and metabolically quiescent.

    “Throughout adulthood, MuSCs, which are generally characterized by expression of the myogenic transcription factor Pax7 (ref. 2), are retained in a mitotically and metabolically quiescent state3,4.”

    From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [3]

  • In many tissues, homeostatic maintenance and regenerative response to injury depend on tissue-specific stem cells.

    “In many tissues, homeostatic tissue maintenance and regenerative responsiveness to injury depend on tissue-specific stem cells—long-lived cells endowed with the capacity to both self-renew and differentiate to produce mature daughters.”

    From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [1]

  • The ability of stem cells to balance quiescence with proliferative activity is critical for their survival and for appropriate physiological and regenerative responses.

    “their ability to balance quiescence with proliferative activity appears to be critical for their survival and maintenance of appropriate physiological and regenerative responses1”

    From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [1]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting claims about p57 and HSC quiescence

    Minor

    The text says p57 deficiency has no effect on HSC quiescence, but the title of its cited reference says p57 is required for that quiescence.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Cheung, T. H., & Rando, T. A.
Affiliations
Stanford Medicine (US)
Corresponding author
Rando, Thomas A.
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2013-05-23
Volume
14
Issue
6
Pages
329-340
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/nrm3591
PMC
PMC3808888
OpenAlex
W2075670261
Semantic Scholar
843ef83cb33fc791b11742d2d434cf25a3e10e70
Cited by
1,148
References
164
Citations by year
2026: 45 · 2025: 72 · 2024: 76 · 2023: 91 · 2022: 95 · 2021: 106 · 2020: 121 · 2019: 115 · 2018: 98 · 2017: 101 · 2016: 91 · 2015: 72 · 2014: 57 · 2013: 8
FWCI
11.60
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Glenn Foundation for Medical Research
  • Muscular Dystrophy Association
  • National Institute on Aging (R37AG023806, R01AG023806, P01AG036695)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062185, R01AR056849)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
adult stem cells, stem cell quiescence, epigenetic regulation, transcriptional regulation, post-transcriptional regulation, signaling pathways, stem cell activation, tissue regeneration, aging
MeSH terms
Aging, Animals, Humans, Regeneration, Transcription, Genetic, Signal Transduction, Epigenesis, Genetic, Adult Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review