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A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance
Open accessAbstract
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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Metadata
- Authors
- Ito, K., Carracedo, A., Weiss, D., Arai, F., Ala, U., Avigan, D. E., Schafer, Z. T., Evans, R. M., Suda, T., Lee, C.-H., & Pandolfi, P. P.
- Venue
- Nature Medicine
- Published
- 2012-08-19
- Volume
- 18
- Issue
- 9
- Pages
- 1350-1358
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2064484411
- Cited by
- 729
- References
- 11
- FWCI
- 23.05
- Type
- journal article
- Language
- en
- Open access
- green
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