Molecular regulation of stem cell quiescence

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.”

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

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.”

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

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“Epigenetic profiling of the H3K4me3 mark in quiescent HFSCs or quiescent MuSCs (T.H.C and T.A.R, unpublished observations) has revealed a number of genes that are marked by this permissive histone mark61,62.”

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

In the paper

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

In the paper

“dysregulation and loss of quiescence often results in an imbalance in progenitor cell populations ultimately leading to stem cell depletion3.”

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

In the paper

“Thus, both stem cells and differentiated cells can reside in a reversible G0 phase.”

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).”

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.”

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

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.”

In the paper

“Recently, evidence has suggested the coexistence of reserve (quiescent) and active (proliferating) stem cell pools in high-turnover tissue compartments2,27.”

What the sources say

• Not checked yetcites [2] Li, L. & Clevers, H. Coexistence of quiescent and active adult stem cells in mammals. Science 327, 542–545 (2010). source
• Not checked yetcites [27] Grompe, M. Tissue stem cells: new tools and functional diversity. Cell Stem Cell 10, 685–689 (2012). source

In the paper

“Now, it is believed that cells, particularly stem cells, adopt the quiescent state to preserve key functional features.”

In the paper

“Such properties allow them to withstand metabolic stress and to preserve genomic integrity over a lifetime.”

In the paper

“Subsets of mammalian adult stem cells reside in the quiescent state for prolonged periods of time.”

• Also stated in: § Abstract · plain

  “A subset of tissue-specific adult stem cells persists in the quiescent state for prolonged periods of time2.”

What the sources say

• Not checked yetcites [2] Li, L. & Clevers, H. Coexistence of quiescent and active adult stem cells in mammals. Science 327, 542–545 (2010). source

In the paper

“we present a model of the quiescent state as a ‘poised state’ rather than a dormant state.”

In the paper

“This state, which is reversible, has long been viewed as dormant and with minimal basal activity.”

• Also stated in: § The diversity of quiescent states · plain

  “Thus, both stem cells and differentiated cells can reside in a reversible G0 phase.”

In the paper

“As a result, tissue replenishment is affected during homeostasis and following damage.”

In the paper

“mature hepatocytes are capable of entering the cell cycle and contribute to liver regeneration in the case of partial hepatectomy13.”

What the sources say

• Not checked yetcites [13] Fausto, N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39, 1477–1487 (2004). source

In the paper

“HSCs are lost when EZH1 is ablated60.”

What the sources say

• Not checked yetcites [60] Hidalgo, I. et al. Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell 11, 649–662 (2012). source

In the paper

“overexpression of EZH2 in HSCs prevents HSC exhaus-tion59”

What the sources say

• Not checked yetcites [59] Kamminga, L. M. et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107, 2170–2179 (2006). source

In the paper

“interconversion of reserve and active intestinal stem cell (ISC) populations has also been observed previously25,28–30.”

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
• Not checked yetcites [28] Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011). Using genetic approaches, this paper demonstrates that quiescent ISCs could be interconverted to active ISCs and displayed stem cell identity. source
• Not checked yetcites [29] Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007). Using knock-in reporter alleles, this paper shows the expression of LGR5 in the crypt in actively cycling basal columnar cells and suggests that LGR5 is a stem cell marker in the intestine, multiple adult tissues and cancers. source
• Not checked yetcites [30] Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010). source

In the paper

“conditional knockouts of the H3K27 methyl-transferases EZH1 and EZH2 in HFSCs revealed an essential role of chromatin modification in hair follicle homeostasis and wound repair57.”

What the sources say

• Not checked yetcites [57] Ezhkova, E. et al. EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 25, 485–498 (2011). Suggests that the H3K27 methyltransferases EZH1 and EZH2 are essential for hair follicle and wound repair and demonstrates an important role of the Polycomb group complex in regulating the hair follicle lineage in an epigenetic manner. source

In the paper

“Chromatin regions that are marked by both H3K4me3 and H3K27me3, which are termed bivalent domains, are frequently located in close proximity to transcription start sites56.”

What the sources say

• Not checked yetcites [56] Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006). source

In the paper

“p53, a master regulator of diverse cellular processes, especially those involved in the maintenance of genomic integrity, has an important role in regulating stem cell quiescence64.”

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

In the paper

“In NSCs, genetic ablation of RB together with p53 triggers NSC over-proliferation, resulting in a brain tumour phenotype68.”

What the sources say

• Not checked yetcites [68] Jacques, T. S. et al. Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. EMBO J. 29, 222–235 (2010). source

In the paper

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

In the paper

“Quiescent stem cells that are responsible for regenerating the hair follicles lie within the bulge of the hair follicles21,31,32”

What the sources say

• Not checked yetcites [21] Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004). Reports a conditional genetic approach by expressing an H2B—GFP fusion protein to label slow-cycling cells and identifies LRCs in the skin. source
• Not checked yetcites [31] Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechol. 22, 411–417 (2004). source
• Not checked yetcites [32] Jaks, V. et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature Genet. 40, 1291–1299 (2008). source

In the paper

“The mechanism by which p53 mediates HSC quiescence is independent of the CDK inhibitor p21”

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

In the paper

“Together, these studies suggest important roles of H3K27 methyltransferases in regulating stem cell quiescence in an epigenetic manner.”

In the paper

“Muscle progenitors that lack RB do not differentiate due to their inability to exit the cell cycle70.”

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

In the paper

“a comparison of gene expression profiles of different types of quiescent stem cells, including HSCs45, MuSCs15 and HFSCs43, reveals a gene signature that is common to these quiescent stem cells (TABLE 1).”

What the sources say

• Not checked yetcites [45] Forsberg, E. C. et al. Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells. PLoS ONE 5, e8785 (2010). source
• Not checked yetcites [15] Fukada, S. et al. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25, 2448–2459 (2007). source
• Not checked yetcites [43] Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004). source

In the paper

“the signature reveals the downregulation of genes that are involved in DNA replication and cell cycle progression.”

What the sources say

• Not checked yetcites [15] Fukada, S. et al. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25, 2448–2459 (2007). source
• Not checked yetcites [43] Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004). source
• Not checked yetcites [45] Forsberg, E. C. et al. Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells. PLoS ONE 5, e8785 (2010). source

In the paper

“which suggests an important role of miRNA pathways in regulating stem cell quiescence post-transcriptionally52.”

What the sources say

• Not checked yetcites [52] Arnold, C. P. et al. microRNA programs in normal and aberrant stem and progenitor cells. Genome Res. 21, 798–810 (2011). source

In the paper

“Early studies of RB revealed that one of its major roles is to inhibit cell cycle progression66.”

What the sources say

• Not checked yetcites [66] Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995). source

In the paper

“adult epidermal homeostasis seems to rely solely on active stem cells34”

What the sources say

• Not checked yetcites [34] Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007). source

In the paper

“In contrast to observations in ES cells, few genes are marked by bivalent domains in lineage-restricted, quiescent HFSCs61.”

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

In the paper

“the tumour suppressor RB, has also been implicated as a regulator of stem cell quiescence.”

In the paper

“Recent epigenetic studies have shed light on how chromatin states contribute to maintaining stem cells in a poised state for lineage progression.”

In the paper

“The cell cycle progresses normally when RB is inactivated by phosphorylation facilitated by different cyclin–CDK complexes67.”

What the sources say

• Not checked yetcites [67] Harbour, J. W. & Dean, D. C. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14, 2393–2409 (2000). source

In the paper

“Examples of genes that are downregulated in all three quiescent cell types (HSCs, MuSCs and HFSCs) include genes encoding cyclin A2, cyclin B1, cyclin E2 and survivin”

What the sources say

• Not checked yetcites [15] Fukada, S. et al. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25, 2448–2459 (2007). source
• Not checked yetcites [43] Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004). source
• Not checked yetcites [45] Forsberg, E. C. et al. Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells. PLoS ONE 5, e8785 (2010). source

In the paper

“miRNA profiling of HSCs, NSCs and MuSCs and their differentiated progenies has led to a common miRNA signature of stem cell activation from quiescence”

What the sources say

• Not checked yetcites [52] Arnold, C. P. et al. microRNA programs in normal and aberrant stem and progenitor cells. Genome Res. 21, 798–810 (2011). source

In the paper

“Lineage tracing experiments have also facilitated the identification of long-lived stem cells in the mammary epithelium36,37 and in glandular epithelia such as that found in the prostate38.”

What the sources say

• Not checked yetcites [36] Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011). source
• Not checked yetcites [37] Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006). source
• Not checked yetcites [38] Ousset, M. et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nature Cell Biol. 14, 1131–1138 (2012). source

In the paper

“the importance of transcript 3′ UTRs as targets for miRNAs suggests that stem cell quiescence is controlled, at least in part, by mechanisms that alter 3′ UTR length and thus the susceptibility to regulation by miRNAs92–95.”

What the sources say

• Not checked yetcites [92] Boutet, S. C. et al. Alternative polyadenylation mediates microRNA regulation of muscle stem cell function. Cell Stem Cell 10, 327–336 (2012). source
• Not checked yetcites [93] Miura, P., Amirouche, A., Clow, C., Bélanger, G. & Jasmin, B. J. Brain-derived neurotrophic factor expression is repressed during myogenic differentiation by miR-206. J. Neurochem. 120, 230–238 (2012). source
• Not checked yetcites [94] Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008). source
• Not checked yetcites [95] Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009). source

In the paper

“the Myf5 (myogenic factor 5) mRNA and its regulatory miRNA miR-31 were found to be sequestered in mRNA ribonucleoprotein particle (mRNP) granules in quiescent MuSCs91.”

What the sources say

• Not checked yetcites [91] Crist, C. G., Montarras, D. & Buckingham, M. Muscle satellite cells are primed for myogenesis but maintain quiescence with sequestration of Myf5 mRNA targeted by microRNA-31 in mRNP granules. Cell Stem Cell 11, 118–126 (2012). source

In the paper

“The reduced number of quiescent stem cells correlates with impaired self-renewal capacity of p21-deficient cells, which ultimately results in an exhaustion of the stem cell pool65,72.”

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

In the paper

“one miRNA, miR-489, is an important regulator of the quiescent state51.”

What the sources say

• Not checked yetcites [51] Cheung, T. H. et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482, 524–528 (2012). Proposes that the miRNA pathway is essential for the maintenance of muscle stem cell quiescence and identifies the quiescence-specific miRNA miR-489 that functions as a regulator of muscle stem cell quiescence by inhibiting DEK. source

In the paper

“In MuSCs, genetic ablation of RBP-J, the DNA binding factor that is essential for mediating canonical Notch signalling, results in a depletion of the quiescent stem cell pool78,79.”

What the sources say

• Not checked yetcites [78] Bjornson, C. R. R. et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 30, 232–242 (2012). source
• Not checked yetcites [79] Mourikis, P. et al. A critical requirement for Notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30, 243–252 (2012). References 78 and 79 demonstrate that Notch signalling has a role in regulating muscle stem cell quiescence, by showing that genetic ablation of RBP-J specifically in quiescent muscle stem cells results in spontaneous cell cycle entry and, ultimately, the depletion of the stem cell pool. source

In the paper

“Notch signalling promotes differentiation of stem cell progeny in the interfollicular epidermis and hair follicles82,83.”

What the sources say

• Not checked yetcites [82] Estrach, S., Cordes, R., Hozumi, K., Gossler, A. & Watt, F. M. Role of the Notch ligand Delta1 in embryonic and adult mouse epidermis. J. Invest. Dermatol. 128, 825–832 (2007). source
• Not checked yetcites [83] Williams, S. E., Beronja, S., Pasolli, H. A. & Fuchs, E. Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470, 353–358 (2011). source

In the paper

“conditional knockout of the miRNA processing factor Dicer triggers spontaneous activation of quiescent MuSCs51.”

What the sources say

• Not checked yetcites [51] Cheung, T. H. et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482, 524–528 (2012). Proposes that the miRNA pathway is essential for the maintenance of muscle stem cell quiescence and identifies the quiescence-specific miRNA miR-489 that functions as a regulator of muscle stem cell quiescence by inhibiting DEK. source

In the paper

“As a result, HSC quiescence is severely impaired75.”

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

In the paper

“3′ UTR length of a transcript can be modified by mechanisms such as alternative splicing or alternative cleavage and polyadenylation96,97.”

What the sources say

• Not checked yetcites [96] Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nature Rev. Mol. Cell. Biol. 10, 741–754 (2009). source
• Not checked yetcites [97] Di Giammartino, D. C., Nishida, K. & Manley, J. L. Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853–866 (2011). source

In the paper

“In HSCs, miR-126 controls stem cell quiescence by attenuating multiple components in the PI3K–AKT signalling pathway88.”

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

In the paper

“These studies suggest that CKIs are functionally important for the maintenance of stem cell quiescence.”

In the paper

“Shortening of 3′ UTRs seems to correlate with proliferation in many cell types94, including aberrant proliferation in the case of cancer cells95 or during somatic cell reprogramming99”

What the sources say

• Not checked yetcites [94] Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008). source
• Not checked yetcites [95] Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009). source
• Not checked yetcites [99] Ji, Z. & Tian, B. Reprogramming of 3' untranslated regions of mRNAs by alternative polyadenylation in generation of pluripotent stem cells from different cell types. PLoS ONE 4, e8419 (2009). source

In the paper

“reducing miR-126 activity allows HSC proliferation without inducing exhaustion88.”

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

In the paper

“miR-489 functions to prevent MuSC proliferation by suppressing the oncogene DEK51,90.”

What the sources say

• Not checked yetcites [51] Cheung, T. H. et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482, 524–528 (2012). Proposes that the miRNA pathway is essential for the maintenance of muscle stem cell quiescence and identifies the quiescence-specific miRNA miR-489 that functions as a regulator of muscle stem cell quiescence by inhibiting DEK. source
• Not checked yetcites [90] Ageberg, M., Gullberg, U. & Lindmark, A. The involvement of cellular proliferation status in the expression of the human proto-oncogene DEK. Haematologica 91, 268–269 (2006).

In the paper

“the quiescent HSC pool is lost when all three RB family proteins are conditionally ablated.”

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

In the paper

“Notch signalling is not required for quiescent HSC maintenance81”

What the sources say

• Not checked yetcites [81] Maillard, I. et al. Canonical Notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2, 356–366 (2008). source

In the paper

“This mode of post-transcriptional regulation has emerged as an important aspect in the control of stem cell quiescence, as recently demonstrated in HSCs88 and MuSCs51.”

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
• Not checked yetcites [51] Cheung, T. H. et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482, 524–528 (2012). Proposes that the miRNA pathway is essential for the maintenance of muscle stem cell quiescence and identifies the quiescence-specific miRNA miR-489 that functions as a regulator of muscle stem cell quiescence by inhibiting DEK. source

In the paper

“T cell activation from the quiescent state is associated with widespread shortening of 3′ UTRs, thereby circumventing the regulatory role of mRNA-targeting miRNAs during activation94.”

What the sources say

• Not checked yetcites [94] Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008). source

In the paper

“In adult NSCs, cell fate is determined by the levels of Notch activity, and quiescence is promoted by high Notch activity80.”

What the sources say

• Not checked yetcites [80] Chapouton, P. et al. Notch activity levels control the balance between quiescence and recruitment of adult neural stem cells. J. Neurosci. 30, 7961–7974 (2010). source

In the paper

“This report suggests that quiescent MuSCs are primed for differentiation, as the storage of mRNAs makes then readily available for the activation of differentiation programmes.”

In the paper

“The loss of quiescence is associated with spontaneous activation and premature differentiation of stem cells78,79”

What the sources say

• Not checked yetcites [78] Bjornson, C. R. R. et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 30, 232–242 (2012). source
• Not checked yetcites [79] Mourikis, P. et al. A critical requirement for Notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30, 243–252 (2012). References 78 and 79 demonstrate that Notch signalling has a role in regulating muscle stem cell quiescence, by showing that genetic ablation of RBP-J specifically in quiescent muscle stem cells results in spontaneous cell cycle entry and, ultimately, the depletion of the stem cell pool. source

In the paper

“In double-knockout mice lacking both p57 and p27, the loss of CKIs promotes nuclear import of the HSC70–cyclin D1 complex and concomitant RB phosphorylation.”

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

In the paper

“There is mounting evidence of asymmetric chromosome segregation in stem cells such as MuSCs17,18,129, ISCs20,130,131 and NSCs132.”

What the sources say

• Not checked yetcites [17] Conboy, M. J., Karasov, A. O. & Rando, T. A. High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol. 5, e102 (2007). source
• Not checked yetcites [18] Shinin, V., Gayraud-Morel, B., Gomès, D. & Tajbakhsh, S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nature Cell Biol. 8, 677–687 (2006). source
• Not checked yetcites [129] Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012). source

In the paper

“In NSCs, FOXO3 regulates the size of the NSC pool108.”

What the sources say

• Not checked yetcites [108] Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source

In the paper

“quiescent MuSCs and HSCs were found viable in post-mortem tissue109.”

What the sources say

• Not checked yetcites [109] Latil, M. et al. Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity. Nature Commun. 3, 903 (2012). source

In the paper

“During normal tissue homeostasis, neither template strand segregation nor label retention was observed in one study of HSCs135.”

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

In the paper

“homologous recombination has been reported to occur more predominantly in proliferating progenitor cells.”

What the sources say

• Not checked yetcites [126] Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010). Proposes that HSCs preferentially use a more error-prone DNA repair mechanism in the quiescent state and that HSCs might accumulate mutations as a consequence. source

In the paper

“Long-lived, non-dividing quiescent stem cells may accumulate damage from environmental stress (for example, oxidative stress caused by the accumulation of reactive oxygen species (ROS)), similarly to any long-lived cell such as a post-mitotic neuron or cardio-myocyte103.”

What the sources say

• Not checked yetcites [103] Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006). source

In the paper

“This suggests that autophagy is essential for maintenance of HSC quiescence122.”

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

In the paper

“Studies of the FOXO family of transcription factors have revealed that this pathway is functionally important in quiescent stem cells to safeguard these cells from environmental stress.”

In the paper

“quiescence is induced when cultured haematopoietic cells are grown under hypoxic conditions113,114.”

What the sources say

• Not checked yetcites [113] Shima, H. et al. Acquisition of G0 state by CD34-positive cord blood cells after bone marrow transplantation. Exp. Hematol. 38, 1231–1240 (2010). source
• Not checked yetcites [114] Hermitte, F., Brunet de la Grange, P., Belloc, F., Praloran, V. & Ivanovic, Z. Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells. Stem Cells 24, 65–73 (2006). source

In the paper

“Homologous recombination uses a long homologous sequence to guide repair in the S phase and G2 phase of the cell cycle, in which sister chromatids are available as templates125.”

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

In the paper

“NSCs devoid of FOXO3 are defective in self-renewal”

What the sources say

• Not checked yetcites [108] Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source

In the paper

“A change in the expression levels of miRNAs can tip the balance and result in repression or activation of many functionally important target genes101,102.”

What the sources say

• Not checked yetcites [101] Stark, A., Brennecke, J., Bushati, N., Russell, R. B. & Cohen, S. M. Animal microRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell 123, 1133–1146 (2005). source
• Not checked yetcites [102] Farh, K. K.-H. et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310, 1817–1821 (2005). source

In the paper

“In mammalian systems, two major mechanisms, namely homologous recombination and non-homologous end-joining (NHEJ), mediate DSB repair124.”

What the sources say

• Not checked yetcites [124] Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004). source

In the paper

“a recent study demonstrated that quiescent HSCs preferentially use NHEJ to repair DSBs126”

What the sources say

• Not checked yetcites [126] Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010). Proposes that HSCs preferentially use a more error-prone DNA repair mechanism in the quiescent state and that HSCs might accumulate mutations as a consequence. source

In the paper

“at least some stem cell populations reside in poorly oxygenated niches110–112”

What the sources say

• Not checked yetcites [110] Mounier, R., Chrétien, F. & Chazaud, B. Blood vessels and the satellite cell niche. Curr. Top. Dev. Biol. 96, 121–138 (2011). source
• Not checked yetcites [111] Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010). source
• Not checked yetcites [112] Parmar, K., Mauch, P., Vergilio, J.-A., Sackstein, R. & Down, J. D. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl Acad. Sci. USA 104, 5431–5436 (2007). source

In the paper

“administration of the antioxidant N-acetyl-L-cysteine is able to rescue this FOXO-deficient phenotype in HSCs107.”

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

In the paper

“The level of HIF1α is important for HSC quiescence115.”

What the sources say

• Not checked yetcites [115] Suda, T., Takubo, K. & Semenza, G. L. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9, 298–310 (2011). source

In the paper

“quiescent stem cells seem to have adopted specific mechanisms to respond to environmental stresses and, thus, to maintain cellular integrity and assure long-term survival.”

In the paper

“Emerging evidence has demonstrated that stem cells in different tissue compartments exhibit template strand segregation during cell divisions128.”

What the sources say

• Not checked yetcites [128] Charville, G. W. & Rando, T. A. Stem cell ageing and non-random chromosome segregation. Phil. Trans. R. Soc., B, Biol. Sci. 366, 85–93 (2011). source

In the paper

“Pol II activity is tightly regulated by phosphorylation of its carboxy-terminal domain (CTD)140.”

What the sources say

• Not checked yetcites [140] Fuda, N. J., Ardehali, M. B. & Lis, J. T. Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 461, 186–192 (2009). source

In the paper

“In various cell types, including ES cells, Pol II often occupies promoter regions and not the gene body.”

What the sources say

• Not checked yetcites [144] Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010). source
• Not checked yetcites [145] Wade, J. T. & Struhl, K. The transition from transcriptional initiation to elongation. Curr. Opin. Genet. Dev. 18, 130–136 (2008). source
• Not checked yetcites [146] Levine, M. Paused RNA polymerase II as a developmental checkpoint. Cell 145, 502–511 (2011). source

In the paper

“This is often followed by the exhaustion of the stem cell pool and results in impaired tissue homeo-stasis and regeneration, highlighting the importance of maintaining stem cell quiescence for tissue and organismal health.”

In the paper

“This is consistent with evidence of promoter-proximal pausing which indicates some form of post-initiation regulation144–146.”

What the sources say

• Not checked yetcites [144] Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010). source
• Not checked yetcites [145] Wade, J. T. & Struhl, K. The transition from transcriptional initiation to elongation. Curr. Opin. Genet. Dev. 18, 130–136 (2008). source
• Not checked yetcites [146] Levine, M. Paused RNA polymerase II as a developmental checkpoint. Cell 145, 502–511 (2011). source

In the paper

“We thus propose that quiescent stem cells are poised for activation by specific energetically favourable mechanisms that are compatible with the low metabolic state of quiescence and that allow for rapid and global responses needed for activation (FIG. 3).”

In the paper

“It seems that quiescent stem cells have the ability to sense environmental changes and respond by re-entering the cell cycle for proliferation.”

In the paper

“From an energetics point of view, it seems favourable for a quiescent stem cell to alter the expression of specific miRNAs, as each of these in turn affect a pool of target genes.”

In the paper

“One such example is the regulation of the quiescent state by miRNAs (see above).”

In the paper

“In one extreme scenario, a quiescent stem cell would maintain the expression of all necessary components that are required for activation and proliferation. However, given the low metabolic state of a quiescent stem cell, this seems unlikely.”

In the paper

“Interestingly, Ser2 phosphorylation of the Pol II CTD is absent in many adult quiescent stem cells, which indicates a lack of transcription elongation in these cells147.”

What the sources say

• Not checked yetcites [147] Freter, R., Osawa, M. & Nishikawa, S. Adult stem cells exhibit global suppression of RNA polymerase II serine-2 phosphorylation. Stem cells 28, 1571–1580 (2010). source

In the paper

“Recent discoveries suggest that the quiescent state is not just a passive state but, instead, actively regulated by different intrinsic mechanisms.”

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.”

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

In the paper

“Interestingly, Ser2 phosphorylation of the Pol II CTD is absent in many adult quiescent stem cells, which indicates a lack of transcription elongation in these cells147.”

What the sources say

• Not checked yetcites [147] Freter, R., Osawa, M. & Nishikawa, S. Adult stem cells exhibit global suppression of RNA polymerase II serine-2 phosphorylation. Stem cells 28, 1571–1580 (2010). source

In the paper

“MYC controls Pol II-mediated elongation and pause release, and it can activate a large number of genes that promote rapid proliferation144.”

What the sources say

• Not checked yetcites [144] Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010). source

In the paper

“It has previously been shown that the miR-16 family of miRNAs has a role in regulating G0 to G1 transition139.”

What the sources say

• Not checked yetcites [139] Linsley, P. S. et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol. Cell. Biol. 27, 2240–2252 (2007). source

In the paper

“This is often followed by the exhaustion of the stem cell pool and results in impaired tissue homeo-stasis and regeneration, highlighting the importance of maintaining stem cell quiescence for tissue and organismal health.”

In the paper

“evidence of asymmetric chromosome segregation was lacking in certain studies of epidermal stem cells136,137 and ISCs138.”

What the sources say

• 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

In the paper

“This is often followed by the exhaustion of the stem cell pool and results in impaired tissue homeo-stasis and regeneration, highlighting the importance of maintaining stem cell quiescence for tissue and organismal health.”

In the paper

“Intriguingly, silencing of transcripts that are downregulated by miR-16 also affects cell cycle progression139.”

What the sources say

• Not checked yetcites [139] Linsley, P. S. et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol. Cell. Biol. 27, 2240–2252 (2007). source

In the paper

“In addition, genes that are necessary for lineage progression can be poised by transcriptional and post-transcriptional mechanisms.”

In the paper

“As demonstrated by studies of different stem cell compartments, one of the consequences of inhibiting essential signalling pathways that maintain the quiescent state is the premature activation or differentiation of stem cells.”

In the paper

“MYC controls Pol II-mediated elongation and pause release, and it can activate a large number of genes that promote rapid proliferation144.”

What the sources say

• Not checked yetcites [144] Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010). source

In the paper

“Transcriptional activation of loci that are marked by H3K4me3 at their transcription start sites may depend on additional trans-criptional and post-transcriptional mechanisms.”