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| Stem Cells: Accelerated ageing
Activation of p38 MAPK in response to reactive oxygen species limits the lifespan of hematopoietic stem cells in vivo. Reactive oxygen species (ROS) and telomere shortening are major regulators of cell senescence. Previous work has shown that ATM (ataxia telangiectasia mutated), a key cell cycle regulator, is required for the self-renewal of hematopoietic stem cells (HSCs) in a telomere-independent manner. The reduced self-renewal capacity of Atm-/- HSCs has been associated with elevated ROS but the precise molecular mechanism involved is unclear. In Nature Medicine, Suda et al. now show that p38 MAPK signaling limits HSC lifespan in response to oxidative stress or ATM deficiency.
The authors show that buthionine sulfoximine (BSO)-induced oxidative stress reduces HSC self-renewal and leads to an increase in the expression of the tumor suppressors p16Ink4a and p19Arf in vitro. As mitogen-activated protein kinase (MAPK) pathways have been implicated in various stress responses as well as in the regulation of p16Ink4a, pharmacological inhibitors were used to examine the contribution of p38 MAPK, ERK and JNK to the ROS-induced increase of p16Ink4a and p19Arf. Treatment with the antioxidant N-acetyl-L-cysteine (NAC) or the p38 MAPK inhibitor SB203580, blocked the effect of ROS on the expression of these markers. p38 MAPK activation was induced by ROS in immature hematopoietic cells, but not in differentiated cell populations, suggesting that activation of p38 MAPK signaling by oxidative stress is HSC-specific. To determine the involvement of p38 MAPK in HSC self renewal in vivo, Suda et al. administered the p38 MAPK inhibitor to Atm-/- mice and examined the repopulation capacity of HSCs after transplantation. When the inhibitor was administered both before and after transplantation, the repopulation activity of Atm-/- HSCs was comparable to wild-type HSCs. Moreover, long term treatment with the p38 MAPK inhibitor was able to prevent the bone marrow failure observed in older Atm-/- mice. It also rescued the quiescence maintenance defect in Atm-/- HSCs, explaining its ability to prevent the observed HSC exhaustion in Atm-/- mice. Interestingly, levels of ROS in HSCs increase with age in wild-type mice. A similar effect is observed when HSCs undergo serial transplantation, a test for HSC self-renewal capacity. Both the decline in repopulation capacity and the activation of p38 MAPK observed in serially transplanted HSCs were prevented by administration of NAC. This study confirms the deleterious effects of oxidative stress on HSC self-renewal, and more importantly, identifies p38 MAPK as a key mediator of ROS-induced HSC lifespan shortening. Whether p38 MAPK activation limits the self-renewal capacity of other stem cell lines remains to be determined, but the ability of NAC to prevent p38 MAPK activation and HSC ageing has very interesting therapeutic implications. Monica Hoyos-Flight
References
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