Signaling Pathways Implicated in Cell Intrinsic HSC Ageing

The fundamental idea that somatic cells have a limited proliferative capacity predicts that HSCs will show decreased functional ability over time, manifesting as stem cell malfunction. Mouse fetal liver HSCs have 1.6 to 3.0 times higher functional ability than young adult HSCs (Chen et al. 1999). Similarly, young mouse HSCs have 1.6 to 2.0 times higher functional ability compared to old mouse HSCs. Human HSCs from fetal liver, cord blood, and adult bone marrow also show a continuous decline in their ability to proliferate in vitro (Chen et al. 1999). This decline in stem cell frequency and function has been attributed to an increase in apoptosis and senescence of the HSC compartment (Chen et al. 1999, Kamminga and de Haan 2006).

The "free radical theory of ageing" proposed by Harman in 1956 suggests that ageing, as well as age-related degenerative diseases, can be attributed to the deleterious effects that free radicals impose on a cell (Harman 1956; see Passos et al., this volume). Thus, long-lived cells run the risk of accumulating damage from oxidative stress as a result of normal metabolism, exposure to cellular toxins, and cellular stress. Ataxia telangiectasia mutated (ATM) is a protein kinase encoded by the ATM gene (Savitsky et al. 1995), which is mutated in the disease ataxia telangiectasia (AT). ATM functions by regulating telomere length, its primary role, and response to cellular damage (Wang et al. 2005). HSCs in ATM-'- mice, as expected, show signs of telomere dysfunction, increased cellular oxidant levels, and reduced numbers of HSCs. This dysfunction in the HSC compartment results in aplasia and severe anemia in mice as early as six months of age. Administration of the hydrogen peroxide scavenger, N-acetyl-cysteine, to ATM-'- mice restores HSC self-renewal and rescues stem cell aplasia. This reversal in stem cell dysfunction is therefore attributed to mechanisms independent of telomere maintenance (Molofsky et al. 2006). Further investigation of ATM showed that it is a stem cell-specific sensor of the levels of reactive oxygen species (ROS). Increased ROS leads to the activation of the p38 MAPK pathway, which normally takes responsibility for general damage control by responding to a variety of stimuli that signal cellular damage (see also Davis and Kipling, this volume). It is constitutively active in the ATM-'- HSCs, causing an increase in HSC proliferation without self-renewal of the stem cell pool. To mimic the replicative stress that HSCs undergo during ageing, serial transplant experiments were performed in both wild-type and ATM-'- mice. With each transplant, the ATM-'- HSCs showed an elevation of ROS and an increase in p38 MAPK pathway activation compared to wild-type. These data are consistent with the hypothesis that stem cells are depleted during the normal ageing process due to an accumulation of ROS, leading to an increase in p38 MAPK signaling, which in turn results in an increase in cell cycling without the critical function of self-renewal (Ito et al. 2006).

Another potential mechanism of stem cell dysfunction with age is an alteration in the damage control pathway of p16INK4a-retinoblastoma (Rb, see Sharpless, this volume). p16INK4a is a cyclin-dependent kinase inhibitor that enforces G1 cell cycle arrest by activating the Rb tumor suppressor, thus inducing irreversible cellular senescence. The Rb pathway is important in HSCs, pancreatic islets, and neural stem cells, making this common mechanism an attractive therapeutic target (Janzen et al. 2006, Krishnamurthy et al. 2006, Molofsky et al. 2006). An increase of p16INK4a with age has been documented in many tissues (Krishnamurthy et al. 2004). At a young age, p16INK4a -'- mice do not show variation in HSC frequency or ability to reconstitute an irradiated host compared to wild-type, but by 14 to 24 months, the p16INK4a -'- mice have higher HSC frequency, increased repopulating ability, and superior engraftment in serial transplants compared to wild-type. Interestingly, when HSCs from young p16INK4a -'- mice are serially transplanted, they undergo premature exhaustion relative to wild-type. Thus, the p16INK4a -'- mouse exhibits a true age-specific phenotype in the stem cell population and, as might be expected, these mice are also cancer-prone (Janzen et al. 2006). These experiments demonstrate the importance of the balance between tissue regeneration and tumorigenesis. The ability of p16INK4a to limit stem cell number, by either senescence or apoptosis, is important in its function as a tumor suppressor. These data highlight the importance p16INK4a in the detection or elimination of damaged cells that are subject to malignant transformation.

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