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.
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。
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References
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
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
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
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
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
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
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
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
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
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
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
Dalton S, 2013. G1 compartmentalization and cell fate coordination. Cell, 155(1):13–14. https://doi.org/10.1016/j.cell.2013.09.015
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Vallier L, 2015. Cell cycle rules pluripotency. Cell Stem Cell, 17(2):131–132. https://doi.org/10.1016/j.stem.2015.07.019
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
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
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
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
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
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
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The study was also supported by the State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
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Project supported by the Ministry of Science and Technology of China (No. 2016YFA0100500), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA16010207), and the National Natural Science Foundation of China (Nos. 31425016, 81530004, and 31830061)
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Gao, Sw., Liu, F. Novel insights into cell cycle regulation of cell fate determination. J. Zhejiang Univ. Sci. B 20, 467–475 (2019). https://doi.org/10.1631/jzus.B1900197
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DOI: https://doi.org/10.1631/jzus.B1900197