title: p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress.
abstract: Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. We do not yet have a clear understanding of how this metabolic activity changes during stress hematopoiesis, such as bone marrow transplantation. Here, we report a critical role for the p38MAPK family isoform p38α in initiating hematopoietic stem and progenitor cell (HSPC) proliferation during stress hematopoiesis in mice. We found that p38MAPK is immediately phosphorylated in HSPCs after a hematological stress, preceding increased HSPC cycling. Conditional deletion of p38α led to defective recovery from hematological stress and a delay in initiation of HSPC proliferation. Mechanistically, p38α signaling increases expression of inosine-5'-monophosphate dehydrogenase 2 in HSPCs, leading to altered levels of amino acids and purine-related metabolites and changes in cell-cycle progression in vitro and in vivo. Our studies have therefore uncovered a p38α-mediated pathway that alters HSPC metabolism to respond to stress and promote recovery.
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Karigane
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ootomo
authors.affiliation: Department of Molecular Metabolic Regulation, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Mashito
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Department of Stem Cell Biology and Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Nagamatsu
authors.affiliation: Department of Vascular Biology, The Sakaguchi Laboratory, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Goda
authors.affiliation: Department of Molecular Metabolic Regulation, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Emi K
authors.initials: EK
authors.lastname: Nishimura
authors.affiliation: Institute for Advanced Biosciences, Keio University, 246-2, Mizukami, Kakuganji, Tsuruoka City, Yamagata 997-0052, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Cardiovascular Division, King's College London, London SE5 9NU, UK.
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan. Electronic address: keiyot@gmail.com.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D004789:Enzyme Activation; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011687:Purines / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D011687:Purines; D017382:Reactive Oxygen Species; D007168:IMP Dehydrogenase; C488212:IMPDH2, mouse; D048051:p38 Mitogen-Activated Protein Kinases