The DOI matches its Crossref record; 164 of the 164 references it cites were found in a registry or an index; none of the 171 sources its claims cite is checked for support yet.
Molecular regulation of stem cell quiescence
Open accessAbstract
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.
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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.
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Claims the paper makes
115 Not checked yet · 27 Own interpretation · 8 No basis given
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Quiescence as a poised state
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Quiescence as a poised state
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Quiescence as a poised state
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“However, it has become increasingly apparent that the use of label retention alone is insufficient to identify adult stem cells.”
§ Molecular regulation of stem cell quiescence > Identification of quiescent stem cells
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In the paper
“dysregulation and loss of quiescence often results in an imbalance in progenitor cell populations ultimately leading to stem cell depletion3.”
§ Molecular regulation of stem cell quiescence > Abstract
What the sources say
- Not checked yetcites [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
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In the paper
“Thus, both stem cells and differentiated cells can reside in a reversible G0 phase.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > The diversity of quiescent states
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In the paper
“Quiescent stem cells are able to respond to stimuli that originate from their niche environment by activating and entering the cell cycle (BOX 2).”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > The diversity of quiescent states
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In the paper
“Subsequent studies demonstrated that sub-optimal conditions such as high cell density7 or serum insufficiency8 could drive cells into this quiescent state.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > Discovery of quiescence
What the sources say
- Not checked yetcites [7] Stoker, M. G. P. The Leeuwenhoek Lecture, 1971: tumour viruses and the sociology of fibroblasts. Proc. R. Soc. Series B, Biol. Sci. 181, 1–17 (1972). source
- Not checked yetcites [8] Temin, H. M. Stimulation by serum of multiplication of stationary chicken cells. J. Cell. Physiol. 78, 161–170 (1971). source
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In the paper
“suggest that quiescence is an actively maintained state in which signalling pathways are involved in maintaining a poised state that allows rapid activation.”
§ Molecular regulation of stem cell quiescence > Abstract
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In the paper
“Recently, evidence has suggested the coexistence of reserve (quiescent) and active (proliferating) stem cell pools in high-turnover tissue compartments2,27.”
§ Molecular regulation of stem cell quiescence > Identification of quiescent stem cells
What the sources say
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- Probably not a substantial claim. 9
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > Discovery of quiescence
What the sources say
- Not checked yetcites [5] Baserga, R. Biochemistry of the cell cycle: a review. Cell Prolifer. 1, 167–191 (1968). source
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In the paper
“Together, these early studies suggested the existence of a quiescent state, access to which is restricted.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > Discovery of quiescence
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In the paper
“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”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > Discovery of quiescence
What the sources say
- Not checked yetcites [9] Pardee, A. B. A restriction point for control of normal animal cell proliferation. Proc. Natl Acad. Sci. USA 71, 1286–1290 (1974). source
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In the paper
“Many unicellular organisms reside in the quiescent state for a prolonged period of time to survive in unfavourable environments11.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > The diversity of quiescent states
What the sources say
- Not checked yetcites [11] Gray, J. V. et al. 'Sleeping beauty': quiescence in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 68, 187–206 (2004). source
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In the paper
“cells in G1 can become quiescent before the R-point but commit to enter a mitotic cell cycle after the R-point9”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > Discovery of quiescence
What the sources say
- Not checked yetcites [9] Pardee, A. B. A restriction point for control of normal animal cell proliferation. Proc. Natl Acad. Sci. USA 71, 1286–1290 (1974). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“studies of seed dormancy revealed that plants utilize this state to preserve the capacity for growth, thereby circumventing an unfavourable environment12.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > The diversity of quiescent states
What the sources say
- Not checked yetcites [12] Amen, R. D. A model of seed dormancy. Bot. Rev. 34, 1–31 (1968). source
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Identification of quiescent stem cells
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > The G0 phase of the cell cycle > Discovery of quiescence
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Epigenetic profiles
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- Rests on an assumption: Quiescent stem cells are generally less differentiated than their proliferating progeny.
In the paper
“quiescent stem cells in the bulge are involved in the process of wound healing but not normal homeostasis35.”
§ Molecular regulation of stem cell quiescence > Identification of quiescent stem cells
What the sources say
- Not checked yetcites [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
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In the paper
“In muscle, deletion of EZH2 impairs MuSC proliferation and derepresses gene expressions of non-muscle lineages58.”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Epigenetic profiles
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Epigenetic profiles
What the sources say
- Not checked yetcites [54] Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome. Cell 128, 669–681 (2007). source
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > p53 and RB protein
What the sources say
- Not checked yetcites [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
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In the paper
“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”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > p53 and RB protein
What the sources say
- Not checked yetcites [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
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In the paper
“it has previously been proposed that H3K4me3 marks genes for transcriptional activation but does not necessarily predict whether these genes are being actively transcribed63.”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Epigenetic profiles
What the sources say
- Not checked yetcites [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
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In the paper
“HSCs that lack cyclin A2 are unable to proliferate in vitro, indicating the essential role of cyclin A2 in HSC proliferation48.”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Transcript profiles
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Epigenetic profiles
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Molecular regulation of stem cell quiescence > Molecular signatures of quiescent stem cells > Transcript profiles
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In the paper
“p53 deficiency in HSCs promotes cell cycle entry with a reduction in the number of quiescent HSCs64.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > p53 and RB protein
What the sources say
- Not checked yetcites [64] Liu, Y. et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4, 37–48 (2009). source
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In the paper
“p21, which is an important regulator of cell cycle progression at G1 that has previously been shown to regulate HSC quiescence65.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > p53 and RB protein
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“inhibition of p27 does not affect the number or self-renewal of HSCs, but increases the size of the haematopoietic progenitor pool73.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > CDK inhibitors (CKIs)
What the sources say
- Not checked yetcites [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
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In the paper
“Notch signalling is involved in tissue maintenance and contributes to cell fate decisions during tissue regeneration76,77.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > Notch signaling
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“This HSC depletion is accompanied by an expansion of early haematopoietic progenitors and an impairment of the reconstitution potential in transplantation experiments71.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > p53 and RB protein
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“inhibition of p21 results in an increase in stem cell proliferation and in a decrease in the quiescent stem cell population65,72.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > CDK inhibitors (CKIs)
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The fact that p57 deficiency has no effect on HSC quiescence might be due to the functional overlap with other CKIs74,75.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > CDK inhibitors (CKIs)
What the sources say
- Not checked yetcites [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 yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“overexpression of miR-126 in HSCs impairs cell cycle entry, resulting in a lower haematopoietic contribu-tion88.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > Post-transcriptional regulation by miRNAs
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“p27 and p57 control nuclear transport of the HSC70–cyclin D1 complex and regulate the cell cycle entry of HSCs75.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > CDK inhibitors (CKIs)
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Many CKIs, including p21, p27 and p57, are expressed in quiescent stem cells and promote cell cycle arrest by inhibiting CDKs (FIG. 1a).”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > CDK inhibitors (CKIs)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“miRNAs bind to the 3′ untranslated region (3′ UTR) of target mRNAs, resulting in their cleavage or trans-lational repression87.”
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > Post-transcriptional regulation by miRNAs
What the sources say
- Not checked yetcites [87] Bartel, D. P. microRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Preservation of genomic integrity
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Preservation of genomic integrity
What the sources say
- Not checked yetcites [123] Lombard, D. B. et al. DNA repair, genome stability, and aging. Cell 120, 497–512 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“asymmetric chromosome segregation does not occur universally in stem cell compartments, and its prevalence may differ depending on the experimental paradigm.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Preservation of genomic integrity
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Metabolic sensors and response mechanisms
What the sources say
- Not checked yetcites [118] Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). source
- Not checked yetcites [119] Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010). source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Whereas NHEJ is an error-prone DNA repair mechanism, homologous recombination is a high-fidelity DSB repair mechanism.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Preservation of genomic integrity
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“NHEJ does not require a template and is predominantly used in G1 phase of the cell cycle125.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Preservation of genomic integrity
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“HSCs in HIF1α-knockout mice are not able to maintain quiescence, and these mice exhibit HSC depletion116.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Metabolic sensors and response mechanisms
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Metabolic sensors and response mechanisms
What the sources say
- Not checked yetcites [118] Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“HSCs depleted of FOXO1, FOXO3 and FOXO4 exhibit a marked increase in ROS and the propensity to exit from quiescence107”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Signalling to protect from environmental stress
What the sources say
- Not checked yetcites [107] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Inhibition of ubiquitin-mediated degradation of HIF1α results in over-stabilization of HIF1α protein and induction of HSC quiescence116”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Metabolic sensors and response mechanisms
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Metabolic sensors and response mechanisms
What the sources say
- Not checked yetcites [118] Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). source
- Not checked yetcites [119] Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010). source
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Survival mechanisms in quiescent cells > Metabolic sensors and response mechanisms
What the sources say
- Not checked yetcites [122] Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Quiescence as a poised state
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Molecular regulation of stem cell quiescence > Quiescence as a poised state
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In view of the epigenetic control of stem cell quiescence, loci required for stem cell activation are possibly marked by permissive histone marks.”
§ Molecular regulation of stem cell quiescence > Quiescence as a poised state
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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”
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?
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Molecular regulation of stem cell quiescence > Molecular regulation of quiescence > CDK inhibitors (CKIs)
“The fact that p57 deficiency has no effect on HSC quiescence might be due to the functional overlap with other CKIs74,75.”
§ Molecular regulation of stem cell quiescence > References
“74. Matsumoto A p57 is required for quiescence and maintenance of adult hematopoietic stem cells Cell Stem Cell 9 262 271 2011”
Citations
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Cited by
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Single-cell transcriptional diversity is a hallmark of developmental potential
Gulati, G. S., Sikandar, S. S., Wesche, D. J., Manjunath, A., Bharadwaj, A., Berger, M. J., Ilagan, F., Kuo, A. H., Hsieh, R. W., Cai, S., et al. (2020) · Science · doi:10.1126/science.aax0249 · Cited by 1,571
Autophagy maintains stemness by preventing senescence
García-Prat, L., Martínez-Vicente, M., Perdiguero, E., Ortet, L., Rodríguez-Ubreva, J., Rebollo, E., Ruiz-Bonilla, V., Gutarra, S., Ballestar, E., Serrano, A. L., et al. (2016) · Nature · doi:10.1038/nature16187 · Cited by 1,355
Extracellular matrix: A dynamic microenvironment for stem cell niche
Gattazzo, F., Urciuolo, A., & Bonaldo, P. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.01.010 · Cited by 1,365
“have to enter the cell cycle, divide and generate a progeny of undifferentiated cells [15,16].”
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Geriatric muscle stem cells switch reversible quiescence into senescence
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Metadata
- Authors
- Cheung, T. H., & Rando, T. A.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Rando, Thomas A.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2013-05-23
- Volume
- 14
- Issue
- 6
- Pages
- 329-340
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- 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
- green
- europepmc.org
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
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A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
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