p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress

Daiki Karigane, Hiroshi Kobayashi, Takayuki Morikawa, Yukako Ootomo, Mashito Sakai, Go Nagamatsu, Yoshiaki Kubota, Nobuhito Goda, Michihiro Matsumoto, Emi K. Nishimura, Tomoyoshi Soga, Kinya Otsu, Makoto Suematsu, Shinichiro Okamoto, Toshio Suda, Keiyo Takubo

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31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)192-204
Number of pages13
JournalCell stem cell
Volume19
Issue number2
DOIs
Publication statusPublished - Aug 4 2016

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Karigane, D., Kobayashi, H., Morikawa, T., Ootomo, Y., Sakai, M., Nagamatsu, G., Kubota, Y., Goda, N., Matsumoto, M., Nishimura, E. K., Soga, T., Otsu, K., Suematsu, M., Okamoto, S., Suda, T., & Takubo, K. (2016). p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress. Cell stem cell, 19(2), 192-204. https://doi.org/10.1016/j.stem.2016.05.013