Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
National Research Council, Institute of Cell Biology and Neurobiology (IBCN), Via del Fosso di Fiorano 64, 00143, Rome, Italy.
Nat Commun. 2018 Mar 29;9(1):1281. doi: 10.1038/s41467-018-03668-0.
Nitric oxide (NO) synthesis is a late event during differentiation of mouse embryonic stem cells (mESC) and occurs after release from serum and leukemia inhibitory factor (LIF). Here we show that after release from pluripotency, a subpopulation of mESC, kept in the naive state by 2i/LIF, expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes NO. This eNOS/NO-positive subpopulation (ESNO+) expresses mesendodermal markers and is more efficient in the generation of cardiovascular precursors than eNOS/NO-negative cells. Mechanistically, production of endogenous NO triggers rapid Hdac2 S-nitrosylation, which reduces association of Hdac2 with the transcriptional repression factor Zeb1, allowing mesendodermal gene expression. In conclusion, our results suggest that the interaction between Zeb1, Hdac2, and eNOS is required for early mesendodermal differentiation of naive mESC.
一氧化氮（NO）合酶的合成是小鼠胚胎干细胞（mESC）分化过程中的晚期事件，发生在血清和白血病抑制因子（LIF）释放之后。在这里，我们表明，在从多能性释放后，由 2i/LIF 维持在原始状态的 mESC 的一个亚群表达内皮型一氧化氮合酶（eNOS）并内源性合成 NO。这个 eNOS/NO 阳性的亚群（ESNO+）表达中胚层和内胚层标记物，并且比 eNOS/NO 阴性细胞更有效地生成心血管前体细胞。从机制上讲，内源性 NO 的产生触发了快速的 Hdac2 S-亚硝基化，从而减少了 Hdac2 与转录抑制因子 Zeb1 的结合，允许中胚层基因表达。总之，我们的结果表明，Zeb1、Hdac2 和 eNOS 之间的相互作用对于原始 mESC 的早期中胚层分化是必需的。
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