Maintaining the HSC Population Stem Cells Make Life or Death Decisions

In addition to factors that influence HSC self-renewal decisions, factors that regulate cellular death and senescence also play an important role in maintaining stem cell homeostasis and may thereby account for differential ageing patterns observed in various inbred mouse strains. Cellular ageing is associated with the accumulation of DNA damage and genomic instability, and it has been hypothesized that proteins regulating DNA-damage response pathways are key regulators of ageing (Dumble et al. 2007). For example, p53 is a tumor suppressor protein that is activated in response to cellular stresses, including DNA damage and oncogenic activation, to induce cell cycle arrest or apoptosis or both. Mice expressing a hyperactive p53 protein display a heightened tumor resistance and, surprisingly, significantly reduced longevity compared to wild-type mice (Tyner et al. 2002). The mutant mice display a generalized organ atrophy and reduced stress tolerance at middle age that progresses with old age. Investigation of the hematopoietic system revealed that aged p53 mutant mice also display a reduced ability to generate white blood cells after ablation of hematopoietic progenitors with 5-flurouracil (Dumble et al. 2007). It was hypothesized that diminished HSC function drove the decrease in regenerative capacity. Additional experiments in this study showed that C57BL/6 mice expressing hyperactive p53 (p53+/m) exhibited no age-associated increases in stem cell number (consistent with wild-type C57BL/6 mice) and in fact showed a reduced number of HSCs compared to age-matched p53+/+ and p53+/- mice. Although the mechanism by which p53 reduces HSC proliferation and function is not yet known, a clear role for p53 activity has been established in the HSC ageing process. One plausible scenario is that altered p53 dosage affects the self-renewal capacity of HSCs, which, over time, results in functional differences in the hemat-opoietic compartments between mutant and wild-type animals (Dumble et al. 2007). The role of altered p53 dosage is now being studied in other stem cell compartments to determine whether the early ageing phenotypes observed in hyperactive p53 mutant mice are a result of a global decline in stem cell function with age.

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