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首页> 美国卫生研究院文献>Journal of Molecular Cell Biology >Esrrb plays important roles in maintaining self-renewal of trophoblast stem cells (TSCs) and reprogramming somatic cells to induced TSCs
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Esrrb plays important roles in maintaining self-renewal of trophoblast stem cells (TSCs) and reprogramming somatic cells to induced TSCs

机译：Esrrb在维持滋养层干细胞（TSC）的自我更新和将体细胞重编程为诱导型TSC中起着重要作用

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摘要

Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.
机译：滋养层干细胞（TSC）可以源自胚泡的滋养外胚层，具有维持自我更新并分化为各种胎盘滋养层细胞类型的能力。同时，通过使用TSC作为细胞模型，可以获得对控制胎盘发育的分子机制的基本见解。 Esrrb是一种转录因子，已显示在胚胎干细胞（ESC）和TSC中都起着关键作用，但是在很大程度上，Esrrb在分化和重编程过程中调节TSC特异性转录组的确切机制仍不清楚。在本研究中，我们阐明了Esrrb在TSC的自我更新和分化以及诱导TSC（iTSC）重编程过程中的功能。我们证明，Esrrb的精确水平对于茎状态的维持和TSC进一步滋养细胞的分化至关重要，因为异位表达的Esrrb可以部分阻止TSC在没有成纤维细胞生长因子4的情况下快速分化。某些关键的TSC特异性转录因子，从而导致TSC的快速分化，而这些Esrrb缺陷型TSC失去了体内出血性病变形成的能力。 Esrrb的功能是通过直接结合并激活一组TSC特异性靶基因（包括Cdx2，Eomes，Sox2，Fgfr4和Bmp4）来发挥的。此外，我们表明Esrrb过表达可以促进MEF到iTSC的转换。此外，Esrrb可以代替Eomes生成GEsTM-iTSC。因此，我们的发现提供了对Esrrb维持TSC自我更新和iTSC重编程过程中分子机制的更好理解。

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