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

Nat Med. 2012 Sep;18(9):1350-8. doi: 10.1038/nm.2882.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Division / physiology*
  • Colony-Forming Units Assay
  • Epoxy Compounds / pharmacology
  • Fatty Acids / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology*
  • Immunoprecipitation
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Models, Biological*
  • Nuclear Proteins / metabolism*
  • Oxidation-Reduction / drug effects
  • PPAR delta / agonists
  • PPAR delta / deficiency
  • PPAR delta / metabolism*
  • Promyelocytic Leukemia Protein
  • Real-Time Polymerase Chain Reaction
  • Thiazoles / pharmacology
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / metabolism*


  • Epoxy Compounds
  • Fatty Acids
  • GW 501516
  • Nuclear Proteins
  • PPAR delta
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Thiazoles
  • Transcription Factors
  • Tumor Suppressor Proteins
  • etomoxir