Hematopoie1ic　stem　cells(HSCs)are　able　to　self-renew　and　to　differentiate　along　all　hematopoietic　lineagesthroughout　the　entire　life-timc　of　organlsm.　Appropriate　control　of　HSC　self-renewal　is　crucial　for　the　mainte-nance　of　hematopoietic　homeostasis.　Here　we　show　that　activation　of　p38MAPK　in　response　to　increasing!evels　of　reactive　oxygen　species (ROS) Iimits　the　lifespan　of　HSCs　in　vivo,　In Atm (-/-) mice,　elevation　of　ROSlevels　induces　HSC-specific　phosphorylation　of　p38MAPK　accompanied　by　a　defect　in　the　maintenance　of　HSCquiescence.　lnhibition　of　p38MAPK　rescued　ROS-induced　defects　in　HSC　repopulating　capacity　and　in　themaintenance　of　HSC　quiescence,　indicating　that　the　ROS-p38MAPK　pathway　contributes　to　exhaustion　of　thestem　cell　population.　Furthermore,　prolonged　treatment　with　an　antioxidant　or　an　inhibitor　of　p38MAPK　ex・tended　the　lifespan　of　HSCs　from　wild・type　mice　in　serial　transplantation　experiments.　These　data　show　thatinactivation　of　p38MAPK　protects　HSCs　against　loss　of self-rcnewal　capacity.

受賞記念講座(三四会奨励賞)