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

K Ito, A Carracedo, D Weiss, F Arai, U Ala, DE Avigan… - Nature medicine, 2012 - nature.com
K Ito, A Carracedo, D Weiss, F Arai, U Ala, DE Avigan, ZT Schafer, RM Evans, T Suda
Nature medicine, 2012nature.com
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 …
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.
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