Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
Stem Cell Reports. 2018 Jul 10;11(1):88-101. doi: 10.1016/j.stemcr.2018.05.008. Epub 2018 Jun 14.
During reprogramming, telomere re-elongation is important for pluripotency acquisition and ensures the high quality of induced pluripotent stem cells (iPSCs), but the regulatory mechanism remains largely unknown. Our study showed that fully reprogrammed mature iPSCs or mouse embryonic stem cells expressed higher levels of miR-590-3p and miR-590-5p than pre-iPSCs. Ectopic expression of either miR-590-3p or miR-590-5p in pre-iPSCs improved telomere elongation and pluripotency. Activin receptor II A (Acvr2a) is the downstream target and mediates the function of miR-590. Downregulation of Acvr2a promoted telomere elongation and pluripotency. Overexpression of miR-590 or inhibition of ACTIVIN signaling increased telomeric repeat binding factor 1 (Terf1) expression. The p-SMAD2 showed increased binding to the Terf1 promoter in pre-iPSCs compared with mature iPSCs. Downregulation of Terf1 blocked miR-590- or shAcvr2a-mediated promotion of telomere elongation and pluripotency in pre-iPSCs. This study elucidated the role of the miR-590/Acvr2a/Terf1 signaling pathway in modulating telomere elongation and pluripotency in pre-iPSCs.
在重编程过程中，端粒的再伸长对于获得多能性至关重要，并确保诱导多能干细胞（iPSC）的高质量，但调控机制在很大程度上仍然未知。我们的研究表明，完全重编程的成熟 iPSC 或小鼠胚胎干细胞比前 iPSC 表达更高水平的 miR-590-3p 和 miR-590-5p。在前 iPSC 中异位表达 miR-590-3p 或 miR-590-5p 可改善端粒伸长和多能性。激活素受体 II A（Acvr2a）是下游靶标，并介导 miR-590 的功能。Acvr2a 的下调促进端粒伸长和多能性。miR-590 的过表达或 ACTIVIN 信号的抑制增加了端粒重复结合因子 1（Terf1）的表达。与成熟 iPSC 相比，p-SMAD2 在前 iPSC 中与 Terf1 启动子的结合增加。Terf1 的下调阻止了 miR-590 或 shAcvr2a 在前 iPSC 中端粒伸长和多能性的促进。本研究阐明了 miR-590/Acvr2a/Terf1 信号通路在调节前 iPSC 中端粒伸长和多能性中的作用。
