A PML–PPAR-? pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.

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.

SUBMITTER: Ito K 

PROVIDER: S-EPMC3566224 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature