脂肪酸氧化的 PML–PPAR-δ 通路调节造血干细胞维持。
A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.
机构信息
Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
出版信息
Nat Med. 2012 Sep;18(9):1350-8. doi: 10.1038/nm.2882.
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.
摘要
干细胞功能是一个高度调控的过程。迄今为止，代谢线索对干细胞功能的贡献还没有被很好地理解。在这里，我们发现了一个以前未知的早幼粒细胞白血病 (PML) - 过氧化物酶体增殖物激活受体 δ (PPAR-δ) - 脂肪酸氧化 (FAO) 途径，用于维持造血干细胞 (HSCs)。我们已经发现，PPAR-δ 的缺失或线粒体 FAO 的抑制会导致 HSC 维持的丧失，而 PPAR-δ 激动剂的治疗则改善了 HSC 的维持。PML 通过调节 PPAR 信号和 FAO 发挥其在 HSC 维持中的重要作用。在机制上，PML-PPAR-δ-FAO 途径控制着 HSCs 的不对称分裂。Ppard 或 Pml 的缺失以及 FAO 的抑制导致 HSC 子细胞的对称承诺，而 PPAR-δ 的激活增加了不对称细胞分裂。因此，我们的发现确定了一种代谢开关，用于控制 HSC 细胞命运，具有潜在的治疗意义。
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