Submitted March 20, 2006
Accepted September 25, 2006
The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging
Melissa Dumble, Lynette Moore, Stuart M Chambers, Hartmut Geiger, Gary Van Zant, Margaret A Goodell, and Lawrence A Donehower*
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY
Departments of Pediatrics and Immunology, Baylor College of Medicine, Houston, TX
Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, TX
* Corresponding author; email: larryd{at}bcm.tmc.edu.
A temporal decline in tissue stem cell functionality may be a key component of mammalian aging. Recently, the tumor suppressor p53 has been implicated as a potential regulator of aging. Here, we examine age-associated hematopoietic stem cell (HSC) dynamics in mice with varying p53 activities. Reduced p53 activity (p53+/-) was associated with higher numbers of proliferating hematopoietic stem and progenitor cells in old age compared to aged wild type 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 (+/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 their p53+/+ and p53+/- counterparts. Moreover, transplantation of 500 HSCs from old p53+/m mice into lethally irradiated recipients resulted in reduced engraftment compared to old wildtype 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.
