Hematopoietic stem cell quiescence maintained by p21cip1/waf1.

Relative quiescence is a defining characteristic of hematopoietic stem cells, while their progeny have dramatic proliferative ability and inexorably move toward terminal differentiation. The quiescence of stem cells has been conjectured to be of critical biologic importance in protecting the stem cell compartment, which we directly assessed using mice engineered to be deficient in the G1 checkpoint regulator, cyclin-dependent kinase inhibitor, p21cip1/waf1 (p21). In the absence of p21, hematopoietic stem cell proliferation and absolute number were increased under normal homeostatic conditions. Exposing the animals to cell cycle-specific myelotoxic injury resulted in premature death due to hematopoietic cell depletion. Further, self-renewal of primitive cells was impaired in serially transplanted bone marrow from p21-/- mice, leading to hematopoietic failure. Therefore, p21 is the molecular switch governing the entry of stem cells into the cell cycle, and in its absence, increased cell cycling leads to stem cell exhaustion. Under conditions of stress, restricted cell cycling is crucial to prevent premature stem cell depletion and hematopoietic death.

[1]  H. Tanke,et al.  Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Donnenberg,et al.  Subcellular and cell-cycle expression profiles of CDK-inhibitors in normal differentiating myeloid cells. , 1999 .

[3]  N. Wolf,et al.  In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection. , 1993, Experimental hematology.

[4]  D. Scadden,et al.  Functional isolation and characterization of human hematopoietic stem cells. , 1995, Science.

[5]  F. Di Cunto,et al.  Inhibitory function of p21Cip1/WAF1 in differentiation of primary mouse keratinocytes independent of cell cycle control. , 1998, Science.

[6]  S. Asano,et al.  Expression of p21Cip1/Waf1/Sdi1 and p27Kip1Cyclin-Dependent Kinase Inhibitors During Human Hematopoiesis , 1999 .

[7]  C. Deng,et al.  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. , 1996, Blood.

[8]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[9]  M. Ogawa,et al.  Differentiation and proliferation of hematopoietic stem cells. , 1993, Blood.

[10]  S. Hellman,et al.  Stem cell self-renewal considerations in bone marrow transplantation. , 1989, Bone marrow transplantation.

[11]  D. Longo,et al.  Recombinant transforming growth factor beta 1 and beta 2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin , 1994, The Journal of experimental medicine.

[12]  Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. , 1999, Blood.

[13]  M. Baert,et al.  Use of limiting-dilution type long-term marrow cultures in frequency analysis of marrow-repopulating and spleen colony-forming hematopoietic stem cells in the mouse. , 1991, Blood.

[14]  James Brugarolas,et al.  Radiation-induced cell cycle arrest compromised by p21 deficiency , 1995, Nature.

[15]  C. Sherr.  G1 phase progression: Cycling on cue , 1994, Cell.

[16]  J. Keller,et al.  Local clonal analysis of the hematopoietic system shows that multiple small short-living clones maintain life-long hematopoiesis in reconstituted mice. , 1996, Blood.

[17]  R. Pyatt,et al.  Functional Heterogeneity of Human CD34+ Cells Isolated in Subcompartments of the G0 /G1 Phase of the Cell Cycle , 1997 .

[18]  R. Hromas,et al.  A positive effect of p21cip1/waf1 in the colony formation from murine myeloid progenitor cells as assessed by retroviral-mediated gene transfer. , 1998, Blood cells, molecules & diseases.

[19]  R. Riblet,et al.  Genetic control of the frequency of hematopoietic stem cells in mice: mapping of a candidate locus to chromosome 1 , 1996, The Journal of experimental medicine.

[20]  K. Walsh,et al.  Resistance to Apoptosis Conferred by Cdk Inhibitors During Myocyte Differentiation , 1996, Science.

[21]  D. Harrison,et al.  Effects of transplantation on the primitive immunohematopoietic stem cell , 1990, The Journal of experimental medicine.

[22]  I. Weissman,et al.  Rapid and sustained hematopoietic recovery in lethally irradiated mice transplanted with purified Thy-1.1lo Lin- Sca-1+ hematopoietic stem cells , 1994 .

[23]  J. R. Smith,et al.  Exit from G0 and entry into the cell cycle of cells expressing p21Sdi1 antisense RNA. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J Sullivan,et al.  Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. , 1995, International journal of radiation oncology, biology, physics.

[25]  D. Harrison,et al.  Hematopoietic precursor cell exhaustion is a cause of proliferative defect in primitive hematopoietic stem cells (PHSC) after chemotherapy. , 1997, Experimental hematology.

[26]  D. Harrison,et al.  Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging , 1978, The Journal of experimental medicine.

[27]  A. Müller,et al.  ES cells have only a limited lymphopoietic potential after adoptive transfer into mouse recipients. , 1993, Development.

[28]  Der,et al.  An in vitro limiting-dilution assay of long-term repopulating hematopoietic stem cells in the mouse. , 1989, Blood.

[29]  D. Harrison,et al.  5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation. , 1990, Experimental hematology.

[30]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[31]  Competitive repopulation: a new assay for long-term stem cell functional capacity. , 1980 .

[32]  R. Pyatt,et al.  Assessment of proliferative and colony-forming capacity after successive in vitro divisions of single human CD34+ cells initially isolated in G0. , 1998, Experimental hematology.

[33]  J. LaBaer,et al.  New functional activities for the p21 family of CDK inhibitors. , 1997, Genes & development.