A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.
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.
Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
Keisuke
K
Ito
Arkaitz
A
Carracedo
Dror
D
Weiss
Fumio
F
Arai
Ugo
U
Ala
David E
DE
Avigan
Zachary T
ZT
Schafer
Ronald M
RM
Evans
Toshio
T
Suda
Chih-Hao
CH
Lee
Pier Paolo
PP
Pandolfi
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D003114:Colony-Forming Units Assay; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D047468:Immunoprecipitation; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D060888:Real-Time Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D004852:Epoxy Compounds; D005227:Fatty Acids; C425931:GW 501516; D009687:Nuclear Proteins; D047494:PPAR delta; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D013844:Thiazoles; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C054207:etomoxir