Abstract
The therapeutic promise of hematopoietic stem cells in medicine has been expanded as broader differentiation potential of the cells has gained experimental support. However, hurdles for stem cell manipulation in vitro and tissue regeneration in vivo remain because of lack of the molecular biology of the stem cells. In particular, elucidating the molecular control of cell cycle entry is necessary for rational stem cell expansion strategies. Understanding how the stem and progenitor cell populations are controlled by negative regulators of cell cycle entry may provide one basis for manipulating these cells. In this mini-review, we focus on the rationale of targeting the cyclin-dependent kinase inhibitors (CKIs) in stem cell biology. Two CKI members, p21Cip1/Waf1 (p21) and p27kip1 (p27), have been shown to govern the pool sizes of hematopoietic stem and progenitor cells, respectively. Of note, their inhibitory roles in primitive hematopoietic cells are distinct from the action of the inhibitory cytokine, transforming growth factor-β1 (TGF-β1). Therefore, the distinct roles of p21, p27, and TGF-β1 in hematopoietic cells offer attractive targets for specific manipulation of the stem or progenitor cell populations in therapeutic strategies.
Similar content being viewed by others
References
Mauch P, Ferrara J, Hellman S. Stem cell self-renewal considerations in bone marrow transplantation.Bone Marrow Transplant. 1989;4:601–607.
Mauch P, Hellman S. Loss of hematopoietic stem cell self-renewal after bone marrow transplantation.Blood. 1989;74:872–875.
Mauch P, Constine L, Greenberger J, et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy.Int J Radiat Oncol Biol Phys. 1995;31:1319–1339.
Gardner RV, Astle CM, Harrison DE. Hematopoietic precursor cell exhaustion is a cause of proliferative defect in primitive hematopoietic stem cells (PHSC) after chemotherapy.Exp Hematol. 1997;25:495–501.
Cheshier SH, Morrison SJ, Liao X, Weissman IL. In vivo proliferation and cell cycle kinetics of long-term self-renewing hemato-poietic stem cells.Proc Natl Acad Sci U S A. 1999;96:3120–3125.
Pawliuk R, Eaves C, Humphries RK. Evidence of both ontogeny and transplant dose-regulated expansion of hematopoietic stem cells in vivo.Blood. 1996;88:2852–2858.
Bradford GB, Williams B, Rossi R, Bertoncello I. Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment.Exp Hematol. 1997;25:445–453.
Abkowitz JL, Catlin SN, Guttorp P. Evidence that hematopoiesis may be a stochastic process in vivo.Nat Med. 1996;2:190–197.
Mahmud N, Devine SM, Weller KP, et al. The relative quiescence of hematopoietic stem cells in nonhuman primates.Blood. 2001;97:3061–3068.
Gothot A, Pyatt R, McMahel J, Rice S, Srour EF. Functional heterogeneity of human CD34(+) cells isolated in subcompartments of the G0/G1 phase of the cell cycle.Blood. 1997;90:4384–4393.
Gothot A, Pyatt R, McMahel J, Rice S, Srour EF. Assessment of proliferative and colony-forming capacity after successive in vitro divisions of single human CD34+ cells initially isolated in G0.Exp Hematol. 1998;26:562–570.
Halstead BW, Tong X, Traycoff CM, Srour EF. Proliferation kinetics and length of cell cycle of individual long-term initiative cells (LTC-IC) [abstract].Exp Hematol. 1998;26:684.
Loeffler M, Potten CS. Stem cells and cellular pedigrees: a conceptual introduction. In: Potten C, ed.Stem Cells. London: Academic Press, 1997:1–27.
Peters SO, Kittler EL, Ramshaw HS, Quesenberry PJ. Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts.Blood. 1996;87:30–37.
Orschell-Traycoff CM, Hiatt K, Dagher RN, Rice S, Yoder MC, Srour EF. Homing and engraftment potential of sca-1(+)lin(-) cells fractionated on the basis of adhesion molecule expression and position in cell cycle.Blood. 2000;96:1380–1387.
Szilvassy SJ, Bass MJ, Van Zant G, Grimes B. Organ-selective homing defines engraftment kinetics of murine hematopoietic stem cells and is compromised by ex vivo expansion.Blood. 1999;93:1557–1566.
Zandstra PW, Lauffenburger DA, Eaves CJ. A ligand-receptor signaling threshold model of stem cell differentiation control: a biologically conserved mechanism applicable to hematopoiesis.Blood. 2000;96:1215–1222.
Yagi M, Ritchie KA, Sitnicka E, Storey C, Roth GJ, Bartelmez S. Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin.Proc Natl Acad Sci U S A. 1999;96:8126–8131.
Dunbar CE, Tisdale J, Yu JM, et al. Transduction of hematopoietic stem cells in humans and in nonhuman primates.Stem Cells. 1997;15:135–139. Discussion: 139-140.
Wu T, Kim HJ, Sellers SE, et al. Prolonged high-level detection of retrovirally marked hematopoietic cells in nonhuman primates after transduction of CD34+ progenitors using clinically feasible methods.Mol Ther. 2000;1:285–293.
Kohn DB, Hershfield MS, Carbonaro D, et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates.Nat Med. 1998;4:775–780.
Kohn DB. Gene therapy for hematopoietic and immune disorders.Bone Marrow Transplant. 1996;18(suppl 3):S55-S58.
Broxmeyer HE, Sherry B, Lu L, et al. Enhancing and suppressing effects of recombinant murine macrophage inflammatory proteins on colony formation in vitro by bone marrow myeloid progenitor cells.Blood. 1990;76:1110–1116.
Hatzfeld J, Li ML, Brown EL, et al. Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides.J Exp Med. 1991;174:925–929.
Keller JR, Mantel C, Sing GK, Ellingsworth LR, Ruscetti SK, Ruscetti FW. Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines.J Exp Med. 1988;168:737–750.
Ruscetti FW, Jacobsen SE, Birchenall-Roberts M, et al. Role of transforming growth factor-beta 1 in regulation of hematopoiesis.Ann N Y Acad Sci. 1991;628:31–43.
Keller JR, McNiece IK, Sill KT, et al. Transforming growth factor beta directly regulates primitive murine hematopoietic cell proliferation.Blood. 1990;75:596–602.
Migdalska A, Molineux G, Demuynck H, Evans GS, Ruscetti F, Dexter TM. Growth inhibitory effects of transforming growth factor-beta 1 in vivo.Growth Factors. 1991;4:239–245.
Cardoso AA, Li ML, Batard P, et al. Release from quiescence of CD34+ CD38- human umbilical cord blood cells reveals their potentiality to engraft adults.Proc Natl Acad Sci U S A. 1993;90:8707–8711.
Hatzfeld A, Batard P, Panterne B, Taieb F, Hatzfeld J. Increased stable retroviral gene transfer in early hematopoietic progenitors released from quiescence.Hum Gene Ther. 1996;7:207–213.
Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT. Functional isolation and characterization of human hematopoietic stem cells.Science. 1995;267:104–108.
Shen H, Cheng T, Preffer FI, et al. Intrinsic human immunodeficiency virus type 1 resistance of hematopoietic stem cells despite coreceptor expression.J Virol. 1999;73:728–737.
Becker PS, Nilsson SK, Li Z, et al. Adhesion receptor expression by hematopoietic cell lines and murine progenitors: modulation by cytokines and cell cycle status.Exp Hematol. 1999;27:533–541.
Roy V, Verfaillie CM. Expression and function of cell adhesion molecules on fetal liver, cord blood and bone marrow hemato-poietic progenitors: implications for anatomical localization and developmental stage specific regulation of hematopoiesis.Exp Hematol. 1999;27:302–312.
Pardee AB.G1 events and regulation of cell proliferation.Science. 1989;246:603–608.
Sherr CJ. G1 phase progression: cycling on cue.Cell. 1994;79:551–555.
Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases.Genes Dev. 1995;9:1149–1163.
Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited.Cancer Res. 2000;60:3689–3695.
Sherr CJ. Cancer cell cycles.Science. 1996;274:1672–1677.
Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression.Genes Dev. 1999;13:1501–1512.
Morgan DO. Principles of CDK regulation.Nature. 1995;374:131–134.
Nakanishi M, Adami GR, Robetorye RS, et al. Exit from G0 and entry into the cell cycle of cells expressing p21Sdi1 antisense RNA.Proc Natl Acad Sci U S A. 1995;92:4352–4356.
Rivard N, L’Allemain G, Bartek J, Pouyssegur J. Abrogation of p27Kip1 by cDNA antisense suppresses quiescence (G0 state) in fibroblasts.J Biol Chem. 1996;271:18337–18341.
Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency.Nature. 1995;377:552–557.
Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dys-plasia, and pituitary tumors.Cell. 1996;85:707–720.
Franklin DS, Godfrey VL, Lee H, et al. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to col-laboratively suppress pituitary tumorigenesis.Genes Dev. 1998;12:2899–2911.
de Nooij JC, Letendre MA, Hariharan IK. A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis.Cell. 1996;87:1237–1247.
de Nooij JC, Hariharan IK. Uncoupling cell fate determination from patterned cell division in the Drosophila eye.Science. 1995;270:983–985.
Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP. p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential.Proc Natl Acad Sci U S A. 1999;96:9089–9094.
Durand B, Fero ML, Roberts JM, Raff MC. p27kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation.Curr Biol. 1998;8:431–440.
Lowenheim H, Furness DN, Kil J, et al. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti.Proc Natl Acad Sci U S A. 1999;96:4084–4088.
Levine EM, Close J, Fero M, Ostrovsky A, Reh TA. p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina.Dev Biol. 2000;219:299–314.
Taniguchi T, Endo H, Chikatsu N, et al. Expression of p21(Cip1/Waf1/Sdi1) and p27(Kip1) cyclin-dependent kinase inhibitors during human hematopoiesis.Blood. 1999;93:4167–4178.
Yaroslavskiy B, Watkins S, Donnenberg AD, Patton TJ, Steinman RA. Subcellular and cell-cycle expression profiles of CDK-inhibitors in normal differentiating myeloid cells.Blood. 1999;93:2907–2917.
Tschan MP, Peters UR, Cajot JF, Betticher DC, Fey MF, Tobler A. The cyclin-dependent kinase inhibitors p18INK4c and p19INK4d are highly expressed in CD34+ progenitor and acute myeloid leukaemic cells but not in normal differentiated myeloid cells.Br J Haematol. 1999;106:644–651.
Marone M, Pierelli L, Mozzetti S, et al. High cyclin-dependent kinase inhibitors in Bcl-2 and Bcl-xL-expressing CD34+-proliferating haematopoietic progenitors.Br J Haematol. 2000;110:654–662.
Cheng T, Shen H, Rodrigues N, Stier S, Scadden DT. Transforming growth factor beta 1 mediates cell-cycle arrest of primitive hemato-poietic cells independent of p21(Cip1/Waf1) or p27(Kip1).Blood. 2001;98:3643–3649.
Ducos K, Panterne B, Fortunel N, Hatzfeld A, Monier MN, Hatzfeld J. p21(cip1) mRNA is controlled by endogenous transforming growth factor-beta1 in quiescent human hematopoietic stem/progenitor cells.J Cell Physiol. 2000;184:80–85.
Dao MA, Hwa J, Nolta JA. Molecular mechanism of transforming growth factor beta-mediated cell-cycle modulation in primary human CD34(+) progenitors.Blood. 2002;99:499–506.
Cheng T, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21(cip1/waf1).Science. 2000;287:1804–1808.
Liu Y, Martindale JL, Gorospe M, Holbrook NJ. Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway.Cancer Res. 1996;56:31–35.
Braun SE, Mantel C, Rosenthal M, et al. A positive effect of p21cip1/waf1 in the colony formation from murine myeloid progenitor cells as assessed by retroviral-mediated gene transfer.Blood Cells Mol Dis. 1998;24:138–148.
LaBaer J, Garrett MD, Stevenson LF, et al. New functional activities for the p21 family of CDK inhibitors.Genes Dev. 1997;11:847–862.
Cheng M, Olivier P, Diehl JA, et al. The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts.Embo J. 1999;18:1571–1583.
Mantel C, Luo Z, Canfield J, Braun S, Deng C, Broxmeyer HE. Involvement of p21cip-1 and p27kip-1 in the molecular mechanisms of steel factor-induced proliferative synergy in vitro and of p21cip-1 in the maintenance of stem/progenitor cells in vivo.Blood. 1996;88:3710–3719.
Conlon I, Raff M. Size control in animal development.Cell. 1999;96:235–244.
Tong X, Srour EF. TGF-β suppresses cell division of Go CD34+ cells while maintaining primitive hematopoietic potential [abstract].Exp Hematol. 1998;26:684.
Dao MA, Taylor N, Nolta JA. Reduction in levels of the cyclin-dependent kinase inhibitor p27(kip-1) coupled with transforming growth factor beta neutralization induces cell-cycle entry and increases retroviral transduction of primitive human hematopoietic cells.Proc Natl Acad Sci U S A. 1998;95:13006–13011.
Coats S, Flanagan WM, Nourse J, Roberts JM. Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle.Science. 1996;272:877–880.
Cheng T, Rodrigues N, Dombkowski D, Stier S, Scadden D. Stem cell repopulation efficiency but not pool size is governed by p27.Nat Med. 2000;6:1235–1240.
Kiyokawa H, Kineman RD, Manova-Todorova KO, et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1).Cell. 1996;85:721–732.
Fero ML, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.Cell. 1996;85:733–744.
Steinman R. Cell cycle regulation and hematopoiesis.Oncogene. In press.
Keller JR, Jacobsen SE, Sill KT, Ellingsworth LR, Ruscetti FW. Stimulation of granulopoiesis by transforming growth factor beta: synergy with granulocyte/macrophage-colony-stimulating factor.Proc Natl Acad Sci U S A. 1991;88:7190–7194.
Jacobsen SE, Ruscetti FW, Dubois CM, Lee J, Boone TC, Keller JR. Transforming growth factor-beta trans-modulates the expression of colony stimulating factor receptors on murine hematopoietic progenitor cell lines.Blood. 1991;77:1706–1716.
Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders.Cell. 2000;103:295–309.
Massague J, Chen YG. Controlling TGF-beta signaling.Genes Dev. 2000;14:627–644.
Fortunel NO, Hatzfeld A, Hatzfeld JA. Transforming growth factor-beta: pleiotropic role in the regulation of hematopoiesis.Blood. 2000;96:2022–2036.
Cashman JD, Clark-Lewis I, Eaves AC, Eaves CJ. Differentiation stage-specific regulation of primitive human hematopoietic progenitor cycling by exogenous and endogenous inhibitors in an in vivo model.Blood. 1999;94:3722–3729.
Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism.Proc Natl Acad Sci U S A. 1995;92:5545–5549.
Landesman Y, Bringold F, Milne DD, Meek DW. Modifications of p53 protein and accumulation of p21 and gadd45 mRNA in TGFbeta 1 growth inhibited cells.Cell Signal. 1997;9:291–298.
Miyazaki M, Ohashi R, Tsuji T, Mihara K, Gohda E, Namba M. Transforming growth factor-beta 1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1.Biochem Biophys Res Commun. 1998;246:873–880.
Li CY, Suardet L, Little JB. Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect.J Biol Chem. 1995;270:4971–4974.
Elbendary A, Berchuck A, Davis P, et al. Transforming growth factor beta 1 can induce CIP1/WAF1 expression independent of the p53 pathway in ovarian cancer cells.Cell Growth Differ. 1994;5:1301–1307.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Cheng, T., Scadden, D.T. Cell Cycle Entry of Hematopoietic Stem and Progenitor Cells Controlled by Distinct Cyclin-Dependent Kinase Inhibitors. Int J Hematol 75, 460–465 (2002). https://doi.org/10.1007/BF02982107
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF02982107