Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.
Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS-p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.
Ito
Keisuke
K
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
Hirao
Atsushi
A
Arai
Fumio
F
Takubo
Keiyo
K
Matsuoka
Sahoko
S
Miyamoto
Kana
K
Ohmura
Masako
M
Naka
Kazuhito
K
Hosokawa
Kentaro
K
Ikeda
Yasuo
Y
Suda
Toshio
T
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580