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Science 10 March 2000:
Vol. 287. no. 5459, pp. 1804 - 1808
DOI: 10.1126/science.287.5459.1804
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Reports

Hematopoietic Stem Cell Quiescence Maintained by p21cip1/waf1

Tao Cheng, 1 Neil Rodrigues, 1 Hongmei Shen, 1 Yong-guang Yang, 2 David Dombkowski, 1 Megan Sykes, 2 David T. Scadden 1*

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 Experimental Hematology, AIDS Research Center, Massachusetts General Hospital Cancer Center,
2 Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
*   To whom correspondence should be addressed at Massachusetts General Hospital, 149 13th Street, Room 5212, Boston, MA 02129, USA. E-mail: scadden.david{at}mgh.harvard.edu

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   Abstract »    Full Text »    PDF »
The Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-dioxin Alters the Circadian Rhythms, Quiescence, and Expression of Clock Genes in Murine Hematopoietic Stem and Progenitor Cells.
R. W. Garrett and T. A. Gasiewicz (2006)
Mol. Pharmacol. 69, 2076-2083
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RAR{gamma} is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.
L. E. Purton, S. Dworkin, G. H. Olsen, C. R. Walkley, S. A. Fabb, S. J. Collins, and P. Chambon (2006)
J. Exp. Med. 203, 1283-1293
   Abstract »    Full Text »    PDF »
The Stem Cell Niche and Bone Metastasis.
G. J. Strewler (2006)
IBMS BoneKEy 3, 19-29
   Abstract »    Full Text »    PDF »
HES1 Inhibits Cycling of Hematopoietic Progenitor Cells via DNA Binding.
X. Yu, J. K. Alder, J. H. Chun, A. D. Friedman, S. Heimfeld, L. Cheng, and C. I. Civin (2006)
Stem Cells 24, 876-888
   Abstract »    Full Text »    PDF »
Lack of {alpha}4 integrin expression in stem cells restricts competitive function and self-renewal activity.
G. V. Priestley, L. M. Scott, T. Ulyanova, and T. Papayannopoulou (2006)
Blood 107, 2959-2967
   Abstract »    Full Text »    PDF »
Stem cells and their niches..
K. A. Moore and I. R. Lemischka (2006)
Science 311, 1880-1885
   Abstract »    Full Text »    PDF »
HOXB4-Induced Self-Renewal of Hematopoietic Stem Cells Is Significantly Enhanced by p21 Deficiency.
N. Miyake, A. C.M. Brun, M. Magnusson, K. Miyake, D. T. Scadden, and S. Karlsson (2006)
Stem Cells 24, 653-661
   Abstract »    Full Text »    PDF »
Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal.
C. C. Zhang, A. D. Steele, S. Lindquist, and H. F. Lodish (2006)
PNAS 103, 2184-2189
   Abstract »    Full Text »    PDF »
Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners.
H. Yu, Y. Yuan, H. Shen, and T. Cheng (2006)
Blood 107, 1200-1206
   Abstract »    Full Text »    PDF »
Expression of Pitx2 in stromal cells is required for normal hematopoiesis.
A. Kieusseian, J. Chagraoui, C. Kerdudo, P.-E. Mangeot, P. J. Gage, N. Navarro, B. Izac, G. Uzan, B. G. Forget, and A. Dubart-Kupperschmitt (2006)
Blood 107, 492-500
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Hematopoietic Stem Cells Are Not the Direct Target of Spontaneous Leukemic Transformation in p18INK4C-Null Reconstituted Mice.
Y. Yuan, H. Yu, M. J. Boyer, X. Song, S. Cao, H. Shen, and T. Cheng (2006)
Cancer Res. 66, 343-351
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Total body irradiation selectively induces murine hematopoietic stem cell senescence.
Y. Wang, B. A. Schulte, A. C. LaRue, M. Ogawa, and D. Zhou (2006)
Blood 107, 358-366
   Abstract »    Full Text »    PDF »
Molecular characterization of melanocyte stem cells in their niche.
M. Osawa, G. Egawa, S.-S. Mak, M. Moriyama, R. Freter, S. Yonetani, F. Beermann, and S.-I. Nishikawa (2005)
Development 132, 5589-5599
   Abstract »    Full Text »    PDF »
Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates.
E. Passegue, A. J. Wagers, S. Giuriato, W. C. Anderson, and I. L. Weissman (2005)
J. Exp. Med. 202, 1599-1611
   Abstract »    Full Text »    PDF »
Induction of Cell Cycle Arrest by Human T-Cell Lymphotropic Virus Type 1 Tax in Hematopoietic Progenitor (CD34+) Cells: Modulation of p21cip1/waf1 and p27kip1 Expression.
A. Tripp, P. Banerjee, M. Sieburg, V. Planelles, F. Li, and G. Feuer (2005)
J. Virol. 79, 14069-14078
   Abstract »    Full Text »    PDF »


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