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

Keisuke Ito; Arkaitz Carracedo; Dror Weiss; Fumio Arai; Ugo Ala; David E. Avigan; Zachary T. Schafer; Ronald M. Evans; Toshio Suda; Chih Hao Lee; Pier Paolo Pandolfi

doi:10.1038/nm.2882

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

Keisuke Ito, Arkaitz Carracedo, Dror Weiss, Fumio Arai, Ugo Ala, David E. Avigan, Zachary T. Schafer, Ronald M. Evans, Toshio Suda, Chih Hao Lee, Pier Paolo Pandolfi

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497 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1350-1358
Number of pages	9
Journal	Nature medicine
Volume	18
Issue number	9
DOIs	https://doi.org/10.1038/nm.2882
Publication status	Published - 2012 Sept
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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title = "A PML-PPAR-δ 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 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.",

author = "Keisuke Ito and Arkaitz Carracedo and Dror Weiss and Fumio Arai and Ugo Ala and Avigan, {David E.} and Schafer, {Zachary T.} and Evans, {Ronald M.} and Toshio Suda and Lee, {Chih Hao} and Pandolfi, {Pier Paolo}",

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AU - Ito, Keisuke

AU - Carracedo, Arkaitz

AU - Weiss, Dror

AU - Arai, Fumio

AU - Ala, Ugo

AU - Avigan, David E.

AU - Schafer, Zachary T.

AU - Evans, Ronald M.

AU - Suda, Toshio

AU - Lee, Chih Hao

AU - Pandolfi, Pier Paolo

PY - 2012/9

Y1 - 2012/9

N2 - 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.

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

Abstract

ASJC Scopus subject areas

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