TY - JOUR
T1 - p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress
AU - Karigane, Daiki
AU - Kobayashi, Hiroshi
AU - Morikawa, Takayuki
AU - Ootomo, Yukako
AU - Sakai, Mashito
AU - Nagamatsu, Go
AU - Kubota, Yoshiaki
AU - Goda, Nobuhito
AU - Matsumoto, Michihiro
AU - Nishimura, Emi K.
AU - Soga, Tomoyoshi
AU - Otsu, Kinya
AU - Suematsu, Makoto
AU - Okamoto, Shinichiro
AU - Suda, Toshio
AU - Takubo, Keiyo
N1 - Funding Information:
We thank J. Koya, M. Yamashita, N. Miyata, M. Tanaka, T. Kitani, and Y.A. Minamishima for advice on analysis and for providing mice; A. Nakamura-Ishizu and E. Lamar for preparation of the manuscript; and M. Haraguchi, S. Tamaki, T. Muraki, K. Endo, M. Katabami-Maie, N. Numata, and T. Hirose for technical support and laboratory management. K.T. was supported in part by KAKENHI grants from MEXT/JSPS (26115005, 15H04861, 16K15507, 26115001, 15K21751), a grant from the National Center for Global Health and Medicine (26-001), AMED-CREST, and grants from the Tokyo Biochemical Research Foundation, the Uehara Memorial Foundation, the Japan Leukemia Research Fund, and the Japan Rheumatism Foundation. T. Suda was supported in part by a MEXT Grant-in-Aid for Scientific Research (S) (26221309). H.K. was a research fellow of the Japan Society for the Promotion of Science.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/8/4
Y1 - 2016/8/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stem.2016.05.013
DO - 10.1016/j.stem.2016.05.013
M3 - Article
C2 - 27345838
AN - SCOPUS:84990902034
SN - 1934-5909
VL - 19
SP - 192
EP - 204
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 2
ER -