The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging

被引:191
作者
Dumble, Melissa
Moore, Lynette
Chambers, Stuart M.
Geiger, Hartmut
Van Zant, Gary
Goodell, Margaret A.
Donehower, Lawrence A.
机构
[1] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Baylor Coll Med, Interdepartmental Program Cell & Mol Biol, Houston, TX 77030 USA
[4] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
[5] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[6] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA
[7] Childrens Hosp, Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA
[8] Univ Kentucky, Markey Canc Ctr, Dept Internal Med, Lexington, KY 40506 USA
关键词
D O I
10.1182/blood-2006-03-010413
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 hernatopoietic stem cell (HSC) dynamics in mice with varying p53 activities. Reduced p53 activity in p53(+/-) mice was associated with higher numbers of proliferating hernatopoietic 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. (Blood. 2007;109:1736-1742) (c) 2007 by The American Society of Hematology.
引用
收藏
页码:1736 / 1742
页数:7
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