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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1736-1742.
Prepublished online as a Blood First Edition Paper on October 10, 2006; DOI 10.1182/blood-2006-03-010413.
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STEM CELLS IN HEMATOLOGY
The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging
Melissa Dumble1,
Lynette Moore2,
Stuart M. Chambers3,4,
Hartmut Geiger5,
Gary Van Zant6,
Margaret A. Goodell3,4,7,8, and
Lawrence A. Donehower1,3
Departments of1 Molecular Virology and Microbiology,
2 Molecular and Cellular Biology,
3 Interdepartmental Program in Cell and Molecular Biology,
4 Center for Cell and Gene Therapy,
7 Pediatrics, and
8 Immunology, Baylor College of Medicine, Houston, TX;
5 Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH;
6 Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
A temporal decline in tissue stem cell functionality may be a key component of mammalian aging. The tumor suppressor p53 has recently been implicated as a potential regulator of aging. We examined age-associated hematopoietic stem cell (HSC) dynamics in mice with varying p53 activities. Reduced p53 activity in p53+/– mice was associated with higher numbers of proliferating hematopoietic stem and progenitor cells in old age compared with aged wild-type (p53+/+) mice. We also assessed HSC dynamics in a p53 mutant mouse model (p53+/m) with higher apparent p53 activity than wild-type mice. The p53 hypermorphic (p53+/m) mice display phenotypes of premature aging. Many aged p53+/m organs exhibit reduced cellularity and atrophy, suggesting defects in stem-cell regenerative capacity. HSC numbers from old p53+/m mice fail to increase with age, unlike those of their p53+/+ and p53+/– counterparts. Moreover, transplantation of 500 HSCs from old p53+/m mice into lethally irradiated recipients resulted in reduced engraftment compared with old wild-type p53+/+ and p53+/– HSCs. Thus, alteration of p53 activity affects stem-cell numbers, proliferation potential, and hematopoiesis in older organisms, supporting a model in which aging is caused in part by a decline in tissue stem cell regenerative function.
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