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

Nature Medicine volume 18, pages 1350–1358 (2012)Cite this article

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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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Figure 1: PPAR-δ is essential for HSC maintenance.
Figure 2: Pharmacological activation of PPAR-δ enhances HSC maintenance.
Figure 3: Pharmacological inhibition of mitochondrial FAO with etomoxir induces HSC exhaustion.
Figure 4: Pharmacological activation of PPAR-δ rescues the maintenance defect of Pml-deleted HSCs.
Figure 5: An immunophenotyping assay to characterize asymmetric division in HSCs.
Figure 6: PPAR-δ and FAO regulate asymmetric division in the HSC compartment.

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Acknowledgements

We thank all the members of the Pandolfi laboratory for comments and discussion. We especially thank K. Hosokawa for technical advice on asymmetric division, M. Alberich-Jorda and A.M. Zubiaga for technical help and critical discussions, and P. Puigserver and M.C. Haigis for technical support with the metabolic analysis. K.I. was supported by a K99 US National Institutes of Health (NIH) grant. The work of A.C. was supported by EMBO, the Ramón y Cajal award (Spanish Ministry of Education), Instituto de Salud Carlos III (PI10/01484), the Marie Curie Reintegration grant (277043) and the Basque Government (PI2012-03). This work was supported by NIH grants to P.P.P.

Author information

Author notes

  1. Keisuke Ito & Arkaitz Carracedo

    Present address: Present addresses: Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research and Departments of Medicine and Cell Biology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA (K.I.), CIC bioGUNE, Technology Park of Bizkaia, Bizkaia, Spain (A.C.) and IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain (A.C.).,

  2. Keisuke Ito and Arkaitz Carracedo: These authors contributed equally to this work.

Authors and Affiliations

  1. Beth Israel Deaconess Cancer Center; Cancer Genetics Program and Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center; and Departments of Medicine and Pathology, Harvard Medical School,

    Keisuke Ito, Arkaitz Carracedo, Dror Weiss, Ugo Ala & Pier Paolo Pandolfi

  2. Cancer Genetics Program and Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Keisuke Ito, Arkaitz Carracedo, Dror Weiss, Ugo Ala & Pier Paolo Pandolfi

  3. Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan

    Fumio Arai & Toshio Suda

  4. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    David E Avigan

  5. Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA

    Zachary T Schafer

  6. Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California, USA

    Ronald M Evans

  7. Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA

    Chih-Hao Lee

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Contributions

K.I., A.C. and P.P.P. conceived of and designed the experiments. K.I., A.C. and D.W. performed the experiments. F.A. and T.S. contributed to the setup of the asymmetric division experiments. U.A. performed the statistical analyses. Z.T.S. helped with the approach of ATP measurement. R.M.E. and C.-H.L. provided Ppard conditional knockout mice. D.E.A. provided expertise in hematology and helped with hematological analysis. K.I., A.C. and P.P.P. analyzed data. K.I., A.C. and P.P.P. wrote the paper.

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Correspondence to Pier Paolo Pandolfi.

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The authors declare no competing financial interests.

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Ito, K., Carracedo, A., Weiss, D. et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 18, 1350–1358 (2012). https://doi.org/10.1038/nm.2882

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