Cell Stem Cell
Volume 19, Issue 2, 4 August 2016, Pages 192-204
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Article
p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress

https://doi.org/10.1016/j.stem.2016.05.013Get rights and content
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Highlights

  • Conditional deletion of p38α disrupts the hematopoietic stem cell stress response

  • Induction of p38α after stress promotes hematopoietic stem cell cycling

  • p38α promotes proliferation by activating purine metabolism

  • Mitf acts downstream of p38α to regulate the purine metabolism pathway gene

Summary

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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