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International Journal of Hematology
Published in: International Journal of Hematology 5/2016

01-05-2016 | Progress in Hematology

Cell cycle regulation of hematopoietic stem or progenitor cells

Authors: Sha Hao, Chen Chen, Tao Cheng

Published in: International Journal of Hematology | Issue 5/2016

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Abstract

The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.
Literature
1.
2.
3.
Giebel B, Bruns I. Self-renewal versus differentiation in hematopoietic stem and progenitor cells: a focus on asymmetric cell divisions. Curr Stem Cell Res Ther. 2008;3(1):9–16.CrossRefPubMed
4.
Weiss CN, Ito K. DNA damage: a sensible mediator of the differentiation decision in hematopoietic stem cells and in leukemia. Int J Mol Sci. 2015;16(3):6183–201.CrossRefPubMedPubMedCentral
5.
Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013;14(6):329–40.CrossRefPubMed
6.
7.
Bradford GB, et al. Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol. 1997;25(5):445–53.PubMed
8.
Tesio M, Trumpp A. Breaking the cell cycle of HSCs by p57 and friends. Cell Stem Cell. 2011;9(3):187–92.CrossRefPubMed
9.
Passegue E, et al. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202(11):1599–611.CrossRefPubMedPubMedCentral
10.
11.
Aleem E, Kaldis P. Mouse models of cell cycle regulators: new paradigms. Results Probl Cell Differ. 2006;42:271–328.CrossRefPubMed
12.
Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.CrossRefPubMed
13.
14.
Siu KT, Minella AC. Developing a systems-based understanding of hematopoietic stem cell cycle control. Adv Exp Med Biol. 2014;844:189–200.CrossRefPubMed
15.
Cheng T, Scadden DT. Cell cycle entry of hematopoietic stem and progenitor cells controlled by distinct cyclin-dependent kinase inhibitors. Int J Hematol. 2002;75(5):460–5.CrossRefPubMed
16.
17.
Boyer MJ, Cheng T. The CDK inhibitors: potential targets for therapeutic stem cell manipulations? Gene Ther. 2008;15(2):117–25.CrossRefPubMed
18.
Palis J, et al. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development. 1999;126(22):5073–84.PubMed
19.
Medvinsky A, Rybtsov S, Taoudi S. Embryonic origin of the adult hematopoietic system: advances and questions. Development. 2011;138(6):1017–31.CrossRefPubMed
20.
Nygren JM, Bryder D, Jacobsen SE. Prolonged cell cycle transit is a defining and developmentally conserved hemopoietic stem cell property. J Immunol. 2006;177(1):201–8.CrossRefPubMed
21.
Cheshier SH, et al. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA. 1999;96(6):3120–5.CrossRefPubMedPubMedCentral
22.
Wilson A, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135(6):1118–29.CrossRefPubMed
23.
Malumbres M, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell. 2004;118(4):493–504.CrossRefPubMed
24.
Jayapal SR, et al. Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress. Haematologica. 2015;100(4):431–8.CrossRefPubMedPubMedCentral
25.
Aleem E, Kiyokawa H, Kaldis P. Cdc2-cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol. 2005;7(8):831–6.CrossRefPubMed
26.
Berthet C, et al. Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Dev Cell. 2006;10(5):563–73.CrossRefPubMed
27.
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153–66.CrossRefPubMed
28.
Santamaria D, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007;448(7155):811–5.CrossRefPubMed
29.
Kozar K, et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell. 2004;118(4):477–91.CrossRefPubMed
30.
Fantl V, et al. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 1995;9(19):2364–72.CrossRefPubMed
31.
32.
33.
34.
35.
36.
Brandeis M, et al. Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc Natl Acad Sci USA. 1998;95(8):4344–9.CrossRefPubMedPubMedCentral
37.
Cheng T, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287(5459):1804–8.CrossRefPubMed
38.
Cheng T, et al. Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Nat Med. 2000;6(11):1235–40.CrossRefPubMed
39.
Furukawa Y, et al. Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation. Br J Haematol. 2000;110(3):663–73.CrossRefPubMed
40.
Serrano M, et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85(1):27–37.CrossRefPubMed
41.
Janzen V, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443(7110):421–6.PubMed
42.
Ito K, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997–1002.CrossRefPubMed
43.
Teofili L, et al. Expression of p15INK4B in normal hematopoiesis. Exp Hematol. 1998;26(12):1133–9.PubMed
44.
Rosu-Myles M, Wolff L. p15Ink4b: dual function in myelopoiesis and inactivation in myeloid disease. Blood Cells Mol Dis. 2008;40(3):406–9.CrossRefPubMed
45.
Untergasser G, et al. Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation. Mech Ageing Dev. 2005;126(1):59–69.CrossRefPubMed
46.
Franklin DS, et al. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev. 1998;12(18):2899–911.CrossRefPubMedPubMedCentral
47.
48.
Yuan Y, et al. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol. 2004;6(5):436–42.CrossRefPubMed
49.
Gao Y, et al. Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nat Commun. 2015;6:6328.CrossRefPubMedPubMedCentral
50.
Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008;9(2):115–28.CrossRefPubMed
51.
Xie XQ, et al. Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion. Sci Rep. 2015;5:18115.CrossRefPubMedPubMedCentral
52.
Gilles L, et al. P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1. Blood. 2008;111(8):4081–91.CrossRefPubMed
53.
Hilpert M, et al. p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging. Stem Cell Reports. 2014;3(6):1085–102.CrossRefPubMedPubMedCentral
54.
Brugarolas J, et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995;377(6549):552–7.CrossRefPubMed
55.
el-Deiry WS, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54(5):1169–74.PubMed
56.
Choudhury AR, et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2007;39(1):99–105.CrossRefPubMed
57.
Nakayama K, et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996;85(5):707–20.CrossRefPubMed
58.
Walkley CR, et al. Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol. 2005;7(2):172–8.CrossRefPubMed
59.
Zou P, et al. p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell. 2011;9(3):247–61.CrossRefPubMed
60.
Yoshihara H, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1(6):685–97.CrossRefPubMed
61.
Yamazaki S, et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 2006;25(15):3515–23.CrossRefPubMedPubMedCentral
62.
Yamazaki S, et al. TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood. 2009;113(6):1250–6.CrossRefPubMed
63.
Matsumoto A, et al. p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell. 2011;9(3):262–71.CrossRefPubMed
64.
van Os R, et al. A Limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning. Stem Cells. 2007;25(4):836–43.CrossRefPubMed
65.
Ganter B, Fu S, Lipsick JS. D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain. EMBO J. 1998;17(1):255–68.CrossRefPubMedPubMedCentral
66.
67.
Nakata Y, et al. c-Myb contributes to G2/M cell cycle transition in human hematopoietic cells by direct regulation of cyclin B1 expression. Mol Cell Biol. 2007;27(6):2048–58.CrossRefPubMedPubMedCentral
68.
69.
70.
71.
Tsai FY, et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994;371(6494):221–6.CrossRefPubMed
72.
Ezoe S, et al. GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21(WAF1) and p27(Kip1) proteins. Blood. 2002;100(10):3512–20.CrossRefPubMed
73.
Kitajima K, et al. GATA-2 and GATA-2/ER display opposing activities in the development and differentiation of blood progenitors. EMBO J. 2002;21(12):3060–9.CrossRefPubMedPubMedCentral
74.
Persons DA, et al. Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis. Blood. 1999;93(2):488–99.PubMed
75.
Hock H, et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature. 2004;431(7011):1002–7.CrossRefPubMed
76.
77.
Antonchuk J, Sauvageau G, Humphries RK. HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation. Exp Hematol. 2001;29(9):1125–34.CrossRefPubMed
78.
Sauvageau G, et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 1995;9(14):1753–65.CrossRefPubMed
79.
Care A, et al. Enforced expression of HOXB7 promotes hematopoietic stem cell proliferation and myeloid-restricted progenitor differentiation. Oncogene. 1999;18(11):1993–2001.CrossRefPubMed
80.
81.
Chen JY, et al. Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature. 2016;530(7589):223–7.CrossRefPubMed
82.
83.
Alexander WS, et al. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood. 1996;87(6):2162–70.PubMed
84.
Qian H, et al. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell. 2007;1(6):671–84.CrossRefPubMed
85.
Abkowitz JL, Chen J. Studies of c-Mpl function distinguish the replication of hematopoietic stem cells from the expansion of differentiating clones. Blood. 2007;109(12):5186–90.CrossRefPubMedPubMedCentral
86.
Larsson J, Karlsson S. The role of Smad signaling in hematopoiesis. Oncogene. 2005;24(37):5676–92.CrossRefPubMed
87.
Chabanon A, et al. A cross-talk between stromal cell-derived factor-1 and transforming growth factor-beta controls the quiescence/cycling switch of CD34(+) progenitors through FoxO3 and mammalian target of rapamycin. Stem Cells. 2008;26(12):3150–61.CrossRefPubMed
88.
Oshima M, Oshima H, Taketo MM. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol. 1996;179(1):297–302.CrossRefPubMed
89.
Larsson J, et al. TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood. 2003;102(9):3129–35.CrossRefPubMed
90.
91.
Zhao M, et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med. 2014;20(11):1321–6.CrossRefPubMed
92.
Han YC, et al. microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia. J Exp Med. 2010;207(3):475–89.CrossRefPubMedPubMedCentral
93.
94.
Herrera-Merchan A, et al. miR-33-mediated downregulation of p53 controls hematopoietic stem cell self-renewal. Cell Cycle. 2010;9(16):3277–85.CrossRefPubMed
95.
96.
Lechman ER, et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell. 2016;29(2):214–28.CrossRefPubMedPubMedCentral
97.
Zuckerman KS, Wicha MS. Extracellular matrix production by the adherent cells of long-term murine bone marrow cultures. Blood. 1983;61(3):540–7.PubMed
98.
Varnum-Finney B, et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood. 1998;91(11):4084–91.PubMed
99.
Wang W, et al. Notch receptor-ligand engagement maintains hematopoietic stem cell quiescence and niche retention. Stem Cells. 2015;33(7):2280–93.CrossRefPubMed
Metadata
Title
Cell cycle regulation of hematopoietic stem or progenitor cells
Authors
Sha Hao
Chen Chen
Tao Cheng
Publication date
01-05-2016
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 5/2016
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-1984-4

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