Molecular regulation of stem cell quiescence

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.”

What the sources say

• Not checked yetcites [5] Baserga, R. Biochemistry of the cell cycle: a review. Cell Prolifer. 1, 167–191 (1968). source

In the paper

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

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”

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

In the paper

“Many unicellular organisms reside in the quiescent state for a prolonged period of time to survive in unfavourable environments11.”

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

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”

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

In the paper

“studies of seed dormancy revealed that plants utilize this state to preserve the capacity for growth, thereby circumventing an unfavourable environment12.”

What the sources say

• Not checked yetcites [12] Amen, R. D. A model of seed dormancy. Bot. Rev. 34, 1–31 (1968). source

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.”

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

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.”

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

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.”

In the paper

“quiescent stem cells in the bulge are involved in the process of wound healing but not normal homeostasis35.”

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

In the paper

“In muscle, deletion of EZH2 impairs MuSC proliferation and derepresses gene expressions of non-muscle lineages58.”

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

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.”

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

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.”

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

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”

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

“it has previously been proposed that H3K4me3 marks genes for transcriptional activation but does not necessarily predict whether these genes are being actively transcribed63.”

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

In the paper

“HSCs that lack cyclin A2 are unable to proliferate in vitro, indicating the essential role of cyclin A2 in HSC proliferation48.”

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

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.”

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

“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).”

In the paper

“p53 deficiency in HSCs promotes cell cycle entry with a reduction in the number of quiescent HSCs64.”

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

“p21, which is an important regulator of cell cycle progression at G1 that has previously been shown to regulate HSC quiescence65.”

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

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.”

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

In the paper

“Notch signalling is involved in tissue maintenance and contributes to cell fate decisions during tissue regeneration76,77.”

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

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.”

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

“inhibition of p21 results in an increase in stem cell proliferation and in a decrease in the quiescent stem cell population65,72.”

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

“The fact that p57 deficiency has no effect on HSC quiescence might be due to the functional overlap with other CKIs74,75.”

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

In the paper

“overexpression of miR-126 in HSCs impairs cell cycle entry, resulting in a lower haematopoietic contribu-tion88.”

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

“p27 and p57 control nuclear transport of the HSC70–cyclin D1 complex and regulate the cell cycle entry of HSCs75.”

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

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

In the paper

“miRNAs bind to the 3′ untranslated region (3′ UTR) of target mRNAs, resulting in their cleavage or trans-lational repression87.”

What the sources say

• Not checked yetcites [87] Bartel, D. P. microRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004). source

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”

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.”

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

In the paper

“asymmetric chromosome segregation does not occur universally in stem cell compartments, and its prevalence may differ depending on the experimental paradigm.”

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

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”

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

In the paper

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

In the paper

“NHEJ does not require a template and is predominantly used in G1 phase of the cell cycle125.”

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

“HSCs in HIF1α-knockout mice are not able to maintain quiescence, and these mice exhibit HSC depletion116.”

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

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.”

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

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.”

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

In the paper

“HSCs depleted of FOXO1, FOXO3 and FOXO4 exhibit a marked increase in ROS and the propensity to exit from quiescence107”

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

“Inhibition of ubiquitin-mediated degradation of HIF1α results in over-stabilization of HIF1α protein and induction of HSC quiescence116”

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

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.”

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

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.”

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

“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

“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.”

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.”