Advertisement

Journal of Zhejiang University-SCIENCE B

, Volume 20, Issue 6, pp 467–475 | Cite as

Novel insights into cell cycle regulation of cell fate determination

  • Su-wei Gao
  • Feng LiuEmail author
Review
  • 10 Downloads

Abstract

The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.

Key words

Cell cycle Cell fate Heterogeneity Fate conversion Stem/progenitor cell 

细胞周期调控细胞命运决定的新见解

概要

长期以来,干/祖细胞由于其具备的自我更新和多 谱系分化能力,因而被视为生物体发育、稳态和 再生过程中的一类重要细胞类型。干/祖细胞自我 更新和多谱系分化之间的平衡是由细胞周期进 程和细胞命运决定之间的协同调控来完成的。大 量研究表明细胞周期状态可以决定细胞的命运, 体现在处于不同细胞周期状态的细胞具有不同 的分子特征和功能。目前,随着高分辨率的表观 基因组学、单细胞转录组学和细胞周期实时标记 系统的开发,我们对细胞周期如何调控细胞命运 有了新的认识。本文总结了细胞周期调控细胞命 运决定和功能异质性的分子机制,以及通过操纵 细胞周期进而影响细胞命运转变的研究进展。这 些发现将加深我们对细胞周期调控细胞命运决 定机制的理解,同时也能促进其在转化医学中的 潜在应用。

关键词

细胞周期 细胞命运 异质性 命运转变 干/祖细胞 

CLC number

Q28 

Notes

Acknowledgments

The study was also supported by the State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

References

  1. Akdemir KC, Jain AK, Allton K, et al., 2014. Genome-wide profiling reveals stimulus-specific functions of p53 during differentiation and DNA damage of human embryonic stem cells. Nucleic Acids Res, 42(1):205–223.  https://doi.org/10.1093/nar/gkt866 Google Scholar
  2. Barnum KJ, O’Connell MJ, 2014. Cell cycle regulation by checkpoints. In: Noguchi E, Gadaleta MC (Eds.), Cell Cycle Control: Methods in Molecular Biology (Methods and Protocols), Vol. 1170. Humana Press, New York, p.29–40.  https://doi.org/10.1007/978-1-4939-0888-2_2 Google Scholar
  3. Besson A, Dowdy SF, Roberts JM, 2008. CDK inhibitors: cell cycle regulators and beyond. Dev Cell, 14(2):159–169.  https://doi.org/10.1016/j.devcel.2008.01.013 Google Scholar
  4. Betschinger J, Nichols J, Dietmann S, et al., 2013. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell, 153(2):335–347.  https://doi.org/10.1016/j.cell.2013.03.012 Google Scholar
  5. Biswas SC, Sanphui P, Chatterjee N, et al., 2017. Cdc25A phosphatase: a key cell cycle protein that regulates neuron death in disease and development. Cell Death Dis, 8(3): e2692.  https://doi.org/10.1038/cddis.2017.115 Google Scholar
  6. Buettner F, Natarajan KN, Casale FP, et al., 2015. Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells. Nat Biotechnol, 33(2):155–160.  https://doi.org/10.1038/nbt.3102 Google Scholar
  7. Calder A, Roth-Albin I, Bhatia S, et al., 2013. Lengthened G1 phase indicates differentiation status in human embryonic stem cells. Stem Cells Dev, 22(2):279–295.  https://doi.org/10.1089/scd.2012.0168 Google Scholar
  8. Chatterjee N, Sanphui P, Kemeny S, et al., 2016. Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation or β-amyloid. Cell Death Discov, 2:16083.  https://doi.org/10.1038/cddiscovery.2016.83 Google Scholar
  9. Cheung TH, Rando TA, 2013. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol, 14(6):329–340.  https://doi.org/10.1038/nrm3591 Google Scholar
  10. Chia NY, Chan YS, Feng B, et al., 2010. A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature, 468(7321):316–320.  https://doi.org/10.1038/nature09531 Google Scholar
  11. Coronado D, Godet M, Bourillot PY, et al., 2013. A short G1 phase is an intrinsic determinant of naïve embryonic stem cell pluripotency. Stem Cell Res, 10(1):118–131.  https://doi.org/10.1016/j.scr.2012.10.004 Google Scholar
  12. Dalton S, 2013. G1 compartmentalization and cell fate coordination. Cell, 155(1):13–14.  https://doi.org/10.1016/j.cell.2013.09.015 Google Scholar
  13. Dalton S, 2015. Linking the cell cycle to cell fate decisions. Trends Cell Biol, 25(10):592–600.  https://doi.org/10.1016/j.tcb.2015.07.007 Google Scholar
  14. Fang JS, Coon BG, Gillis N, et al., 2017. Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nat Commun, 8:2149.  https://doi.org/10.1038/s41467-017-01742-7 Google Scholar
  15. Gonzales KA, Liang HQ, Lim YS, et al., 2015. Deterministic restriction on pluripotent state dissolution by cell-cycle pathways. Cell, 162(3):564–579.  https://doi.org/10.1016/j.cell.2015.07.001 Google Scholar
  16. Gruenheit N, Parkinson K, Brimson CA, et al., 2018. Cell cycle heterogeneity can generate robust cell type proportioning. Dev Cell, 47(4):494–508.e4.  https://doi.org/10.1016/j.devcel.2018.09.023 Google Scholar
  17. Gurdon JB, 2016. Cell fate determination by transcription factors. Curr Top Dev Biol, 116:445–454.  https://doi.org/10.1016/bs.ctdb.2015.10.005 Google Scholar
  18. Haas S, Trumpp A, Milsom MD, 2018. Causes and consequences of hematopoietic stem cell heterogeneity. Cell Stem Cell, 22(5):627–638.  https://doi.org/10.1016/j.stem.2018.04.003 Google Scholar
  19. Harper JW, Adami GR, Wei N, et al., 1993. The p21 Cdkinteracting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 75(4):805–816.  https://doi.org/10.1016/0092-8674(93)90499-G Google Scholar
  20. Hartwell LH, Weinert TA, 1989. Checkpoints: controls that ensure the order of cell cycle events. Science, 246(4930): 629–634.  https://doi.org/10.1126/science.2683079 Google Scholar
  21. Haug JS, He XC, Grindley JC, et al., 2008. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell, 2(4):367–379.  https://doi.org/10.1016/j.stem.2008.01.017 Google Scholar
  22. Ito K, Suda T, 2014. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol, 15(4):243–256.  https://doi.org/10.1038/nrm3772 Google Scholar
  23. Jiang HB, Xu ZM, Zhong P, et al., 2015. Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Nat Commun, 6:10100.  https://doi.org/10.1038/ncomms10100 Google Scholar
  24. Johnson A, Skotheim JM, 2013. Start and the restriction point. Curr Opin Cell Biol, 25(6):717–723.  https://doi.org/10.1016/j.ceb.2013.07.010 Google Scholar
  25. Kar S, Wang MF, Yao W, et al., 2006. PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo. Mol Cancer Ther, 5(6): 1511–1519.  https://doi.org/10.1158/1535-7163.Mct-05-0485 Google Scholar
  26. Koledova Z, Kafkova LR, Calabkova L, et al., 2010. Cdk2 inhibition prolongs G1 phase progression in mouse embryonic stem cells. Stem Cells Dev, 19(2):181–194.  https://doi.org/10.1089/scd.2009.0065 Google Scholar
  27. Lange C, Huttner WB, Calegari F, 2009. Cdk4/cyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors. Cell Stem Cell, 5(3):320–331.  https://doi.org/10.1016/j.stem.2009.05.026 Google Scholar
  28. Lauridsen FKB, Jensen TL, Rapin N, et al., 2018. Differences in cell cycle status underlie transcriptional heterogeneity in the HSC compartment. Cell Rep, 24(3):766–780.  https://doi.org/10.1016/jxelrep.2018.06.057 Google Scholar
  29. Lee MH, Reynisdóttir I, Massagué J, 1995. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev, 9(6):639–649.  https://doi.org/10.1101/gad.9.6.639 Google Scholar
  30. Lein E, Borm LE, Linnarsson S, 2017. The promise of spatial transcriptomics for neuroscience in the era of molecular cell typing. Science, 358(6359):64–69.  https://doi.org/10.1126/science.aan6827 Google Scholar
  31. Li LH, Clevers H, 2010. Coexistence of quiescent and active adult stem cells in mammals. Science, 327(5965):542–545.  https://doi.org/10.1126/science.1180794 Google Scholar
  32. Lim S, Kaldis P, 2013. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development, 140(15):3079–3093.  https://doi.org/10.1242/dev.091744 Google Scholar
  33. Lis R, Karrasch CC, Poulos MG, et al., 2017. Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature, 545(7655):439–445.  https://doi.org/10.1038/nature22326 Google Scholar
  34. Liu ZQ, Wang L, Welch JD, et al., 2017. Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature, 551(7678):100–104.  https://doi.org/10.1038/nature24454 Google Scholar
  35. Lu CJ, Fan XY, Guo YF, et al., 2019. Single-cell analyses identify distinct and intermediate states of zebrafish pancreatic islet development. J Mol Cell Biol, mjy064.  https://doi.org/10.1093/jmcb/mjy064
  36. Lu YC, Sanada C, Xavier-Ferrucio J, et al., 2018. The molecular signature of megakaryocyte-erythroid progenitors reveals a role for the cell cycle in fate specification. Cell Rep, 25(8):2083–2093.e4.  https://doi.org/10.1016/j.celrep.2018.10.084 Google Scholar
  37. Lugert S, Basak O, Knuckles P, et al., 2010. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell, 6(5):445–456.  https://doi.org/10.1016/j.stem.2010.03.017 Google Scholar
  38. Ma YQ, Kanakousaki K, Buttitta L, 2015. How the cell cycle impacts chromatin architecture and influences cell fate. Front Genet, 6:19.  https://doi.org/10.3389/fgene.2015.00019 Google Scholar
  39. Maimets T, Neganova I, Armstrong L, et al., 2008. Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells. Oncogene, 27(40):5277–5287.  https://doi.org/10.1038/onc.2008.166 Google Scholar
  40. Matson JP, Cook JG, 2017. Cell cycle proliferation decisions: the impact of single cell analyses. FEBS J, 284(3):362–375.  https://doi.org/10.1111/febs.13898 Google Scholar
  41. Matsuoka S, Edwards MC, Bai C, et al., 1995. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev, 9(6):650–662.  https://doi.org/10.1101/gad.9.6.650 Google Scholar
  42. McDavid A, Finak G, Gottardo R, 2016. The contribution of cell cycle to heterogeneity in single-cell RNA-seq data. Nat Biotechnol, 34(6):591–593.  https://doi.org/10.1038/nbt.3498 Google Scholar
  43. Mende N, Kuchen EE, Lesche M, et al., 2015. CCND1-CDK4-mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo. J Exp Med, 212(8):1171–1183.  https://doi.org/10.1084/jem.20150308 Google Scholar
  44. Nagano T, Lubling Y, Stevens TJ, et al., 2013. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature, 502(7469):59–64.  https://doi.org/10.1038/nature12593 Google Scholar
  45. Nagano T, Lubling Y, Várnai C, et al., 2017. Cell-cycle dynamics of chromosomal organization at single-cell resolution. Nature, 547(7661):61–67.  https://doi.org/10.1038/nature23001 Google Scholar
  46. Ohnuma S, Harris WA, 2003. Neurogenesis and the cell cycle. Neuron, 40(2):199–208.  https://doi.org/10.1016/S0896-6273(03)00632-9 Google Scholar
  47. Orford KW, Scadden DT, 2008. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet, 9(2):115–128.  https://doi.org/10.1038/nrg2269 Google Scholar
  48. Otsuki L, Brand AH, 2018. Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science, 360(6384):99–102.  https://doi.org/10.1126/science.aan8795 Google Scholar
  49. Pauklin S, Vallier L, 2013. The cell-cycle state of stem cells determines cell fate propensity. Cell, 155(1):135–147.  https://doi.org/10.1016/j.cell.2013.08.031 Google Scholar
  50. Pietenpol JA, Stewart ZA, 2002. Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology, 181–182:475–481.  https://doi.org/10.1016/S0300-483X(02)00460-2 Google Scholar
  51. Polyak K, Lee MH, Erdjument-Bromage H, et al., 1994. Cloning of p27kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell, 78(1):59–66.  https://doi.org/10.1016/0092-8674(94)90572-X Google Scholar
  52. Qian PX, He XC, Paulson A, et al., 2016. The Dlk1-Gtl2 locus preserves LT-HSC function by inhibiting the PI3K-mTOR pathway to restrict mitochondrial metabolism. Cell Stem Cell, 18(2):214–228.  https://doi.org/10.1016/j.stem.2015.11.001 Google Scholar
  53. Roccio M, Schmitter D, Knobloch M, et al., 2013. Predicting stem cell fate changes by differential cell cycle progression patterns. Development, 140(2):459–470.  https://doi.org/10.1242/dev.086215 Google Scholar
  54. Sakaue-Sawano A, Kurokawa H, Morimura T, et al., 2008. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell, 132(3):487–498.  https://doi.org/10.1016/j.cell.2007.12.033 Google Scholar
  55. Salazar-Roa M, Malumbres M, 2017. Fueling the cell division cycle. Trends Cell Biol, 27(1):69–81.  https://doi.org/10.1016/j.tcb.2016.08.009 Google Scholar
  56. Salomoni P, Calegari F, 2010. Cell cycle control of mammalian neural stem cells: putting a speed limit on G1. Trends Cell Biol, 20(5):233–243.  https://doi.org/10.1016/j.tcb.2010.01.006 Google Scholar
  57. Sela Y, Molotski N, Golan S, et al., 2012. Human embryonic stem cells exhibit increased propensity to differentiate during the G1 phase prior to phosphorylation of retinoblastoma protein. Stem Cells, 30(6):1097–1108.  https://doi.org/10.1002/stem.1078 Google Scholar
  58. Sherr CJ, Roberts JM, 1999. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev, 13(12):1501–1512.  https://doi.org/10.1101/gad.13.12.1501 Google Scholar
  59. Singh AM, Chappell J, Trost R, et al., 2013. Cell-cycle control of developmentally regulated transcription factors accounts for heterogeneity in human pluripotent cells. Stem Cell Rep, 1(6):532–544.  https://doi.org/10.1016/j.stemcr.2013.10.009 Google Scholar
  60. Singh AM, Sun YH, Li L, et al., 2015. Cell-cycle control of bivalent epigenetic domains regulates the exit from pluripotency. Stem Cell Rep, 5(3):323–336.  https://doi.org/10.1016/j.stemcr.2015.07.005 Google Scholar
  61. Skinner SO, Xu H, Nagarkar-Jaiswal S, et al., 2016. Single-cell analysis of transcription kinetics across the cell cycle. eLife, 5:e12175.  https://doi.org/10.7554/eLife.12175 Google Scholar
  62. Su TY, Stanley G, Sinha R, et al., 2018. Single-cell analysis of early progenitor cells that build coronary arteries. Nature, 559(7714):356–362.  https://doi.org/10.1038/s41586-018-0288-7 Google Scholar
  63. Sun N, Yu XM, Li F, et al., 2017. Inference of differentiation time for single cell transcriptomes using cell population reference data. Nat Commun, 8(1):1856.  https://doi.org/10.1038/s41467-017-01860-2 Google Scholar
  64. Thomson I, Gilchrist S, Bickmore WA, et al., 2004. The radial positioning of chromatin is not inherited through mitosis but is established de novo in early G1. Curr Biol, 14(2): 166–172.  https://doi.org/10.1016/j.cub.2003.12.024 Google Scholar
  65. Tomás-Loba A, Manieri E, González-Terán B, et al., 2019. p38γ is essential for cell cycle progression and liver tumorigenesis. Nature, 568(7753):557–560.  https://doi.org/10.1038/s41586-019-1112-8 Google Scholar
  66. Toyoshima H, Hunter T, 1994. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell, 78(1):67–74.  https://doi.org/10.1016/0092-8674(94)90573-8 Google Scholar
  67. Upadhaya S, Sawai CM, Papalexi E, et al., 2018. Kinetics of adult hematopoietic stem cell differentiation in vivo. J Exp Med, 215(11):2815–2832.  https://doi.org/10.1084/jem.20180136 Google Scholar
  68. Vallier L, 2015. Cell cycle rules pluripotency. Cell Stem Cell, 17(2):131–132.  https://doi.org/10.1016/j.stem.2015.07.019 Google Scholar
  69. Vierbuchen T, Ostermeier A, Pang ZP, et al., 2010. Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463(7284):1035–1041.  https://doi.org/10.1038/nature08797 Google Scholar
  70. Walter D, Lier A, Geiselhart A, et al., 2015. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature, 520(7548):549–552.  https://doi.org/10.1038/nature14131 Google Scholar
  71. Xie HF, Ye M, Feng R, et al., 2004. Stepwise reprogramming of B cells into macrophages. Cell, 117(5):663–676.  https://doi.org/10.1016/S0092-8674(04)00419-2 Google Scholar
  72. Zerjatke T, Gak IA, Kirova D, et al., 2017. Quantitative cell cycle analysis based on an endogenous all-in-one reporter for cell tracking and classification. Cell Rep, 19(9): 1953–1966.  https://doi.org/10.1016/j.celrep.2017.05.022 Google Scholar
  73. Zetterberg A, Larsson O, Wiman KG, 1995. What is the restriction point? Curr Opin Cell Biol, 7(6):835–842.  https://doi.org/10.1016/0955-0674(95)80067-0 Google Scholar
  74. Zhang MY, Dong Y, Hu FX, et al., 2018. Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes. Nat Immunol, 19(3):279–290.  https://doi.org/10.1038/s41590-018-0046-x Google Scholar

Copyright information

© Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Membrane Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina
  2. 2.Institute for Stem Cell and RegenerationChinese Academy of SciencesBeijingChina
  3. 3.University of Chinese Academy of SciencesBeijingChina

Personalised recommendations