The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging.
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.
Dumble
Melissa
M
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, and Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH, USA.
Moore
Lynette
L
Chambers
Stuart M
SM
Geiger
Hartmut
H
Van Zant
Gary
G
Goodell
Margaret A
MA
Donehower
Lawrence A
LA
D000375:Aging; D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53