A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance

Keisuke Ito, Arkaitz Carracedo, Dror Weiss, Fumio Arai, Ugo Ala, David E. Avigan, Zachary T. Schafer, Ronald M. Evans, Toshio Suda, Chih Hao Lee, Pier Paolo Pandolfi

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351 Citations (Scopus)

Abstract

Stem-cell function is an exquisitely regulated process. Thus far, the contribution of metabolic cues to stem-cell function has not been well understood. Here we identify a previously unknown promyelocytic leukemia (PML)-peroxisome proliferator-activated receptor δ (PPAR-δ)-fatty- acid oxidation (FAO) pathway for the maintenance of hematopoietic stem cells (HSCs). We have found that loss of PPAR-δ or inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-δ agonists improved HSC maintenance. PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, the PML-PPAR-δ-FAO pathway controls the asymmetric division of HSCs. Deletion of Ppard or Pml as well as inhibition of FAO results in the symmetric commitment of HSC daughter cells, whereas PPAR-δ activation increased asymmetric cell division. Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.

Original languageEnglish
Pages (from-to)1350-1358
Number of pages9
JournalNature medicine
Volume18
Issue number9
DOIs
Publication statusPublished - 2012 Sep

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ito, K., Carracedo, A., Weiss, D., Arai, F., Ala, U., Avigan, D. E., Schafer, Z. T., Evans, R. M., Suda, T., Lee, C. H., & Pandolfi, P. P. (2012). A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature medicine, 18(9), 1350-1358. https://doi.org/10.1038/nm.2882