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首页> 外文期刊>Cell metabolism >MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus
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MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus

机译：MSC移植通过狼疮Notch信号的表观遗传调控改善骨质减少

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摘要

Mesenchymal stem cell transplantation (MSCT) has been used to treat human diseases, but the detailed mechanisms underlying its success are not fully understood. Here we show that MSCT rescues bone marrow MSC (BMMSC) function and ameliorates osteopenia in Fas-deficient-MRL/lpr mice. Mechanistically, we show that Fas deficiency causes failure of miR-29b release, thereby elevating intracellular miR-29b levels, and downregulates DNA methyltransferase 1 (Dnmt1) expression in MRL/lpr BMMSCs. This results in hypomethylation of the Notch1 promoter and activation of Notch signaling, in turn leading to impaired osteogenic differentiation. Furthermore, we show that exosomes, secreted due to MSCT, transfer Fas to recipient MRL/lpr BMMSCs to reduce intracellular levels of miR-29b, which results in recovery of Dnmt1-mediated Notch1 promoter hypomethylation and thereby improves MRL/lpr BMMSC function. Collectively our findings unravel the means by which MSCT rescues MRL/lpr BMMSC function through reuse of donor exosome-provided Fas to regulate the miR-29b/Dnmt1/Notch epigenetic cascade.
机译：间充质干细胞移植（MSCT）已用于治疗人类疾病，但其成功所依据的详细机制尚未得到充分了解。在这里，我们显示MSCT可以挽救Fas缺乏型MLR / lpr小鼠的骨髓MSC（BMMSC）功能并改善骨质减少。从机制上讲，我们显示Fas缺乏会导致miR-29b释放失败，从而升高细胞内miR-29b的水平，并下调MRL / lpr BMMSC中的DNA甲基转移酶1（Dnmt1）表达。这导致Notch1启动子的低甲基化和Notch信号的激活，进而导致成骨分化受损。此外，我们显示由于MSCT分泌的外泌体将Fas转移至受体MRL / lpr BMMSC，以降低miR-29b的细胞内水平，从而导致Dnmt1介导的Notch1启动子低甲基化的恢复，从而改善MRL / lpr BMMSC的功能。总的来说，我们的发现揭示了MSCT通过重新利用供体外来体提供的Fas来调节miR-29b / Dnmt1 / Notch表观遗传级联来拯救MRL / lpr BMMSC功能的方法。

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