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- Title
A PML-PPAR-? pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.
- Authors
Ito, Keisuke; Carracedo, Arkaitz; Weiss, Dror; Arai, Fumio; Ala, Ugo; Avigan, David E; Schafer, Zachary T; Evans, Ronald M; Suda, Toshio; Lee, Chih-Hao; Pandolfi, Pier Paolo
- 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 ? (PPAR-?)-fatty-acid oxidation (FAO) pathway for the maintenance of hematopoietic stem cells (HSCs). We have found that loss of PPAR-? or inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-? agonists improved HSC maintenance. PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, the PML-PPAR-?-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-? activation increased asymmetric cell division. Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.
- Subjects
FATTY acid oxidation; HEMATOPOIETIC stem cells; MYELOID leukemia; PEROXISOME proliferator-activated receptors; CELL division; MITOCHONDRIA
- Publication
Nature Medicine, 2012, Vol 18, Issue 9, p1350
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.2882