Format

Send to

Choose Destination
Cell Stem Cell. 2016 Aug 4;19(2):192-204. doi: 10.1016/j.stem.2016.05.013. Epub 2016 Jun 23.

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

Author information

1
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.
2
Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
3
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.
4
Department of Molecular Metabolic Regulation, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
5
Department of Stem Cell Biology and Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
6
Department of Vascular Biology, The Sakaguchi Laboratory, Keio University School of Medicine, Tokyo 160-8582, Japan.
7
Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
8
Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
9
Institute for Advanced Biosciences, Keio University, 246-2, Mizukami, Kakuganji, Tsuruoka City, Yamagata 997-0052, Japan.
10
Cardiovascular Division, King's College London, London SE5 9NU, UK.
11
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
12
Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
13
Cancer Science Institute, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
14
Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan. Electronic address: keiyot@gmail.com.

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.

PMID:
27345838
DOI:
10.1016/j.stem.2016.05.013
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center