BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence
BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence
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DOI：
10.1073/pnas.1603668113
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发表时间：
2016-11-15
影响因子：
11.1
通讯作者：
Yamanaka, Shinya
中科院分区：
文献类型：
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作者：
Hayashi, Yohei;Hsiao, Edward C.;Yamanaka, Shinya
进行性骨化性纤维发育不良（FOP）患者携带ACVR 1 [617 G> A（R206 H）]中的错义突变，导致BMP-SMAD信号转导过度激活。与以前的研究相反，在这里，我们表明FOP成纤维细胞显示出诱导多能干细胞（iPSC）生成效率的提高。这种积极作用被BMP-SMAD信号传导抑制剂（Dorsomorphin或LDN 1931890）或转导抑制性SMAD（SMAD 6或SMAD 7）减弱。在正常成纤维细胞中，通过在重编程期间的早期转导突变体ACVR 1（617 G> A）或SMAD 1或添加BMP 4蛋白来增强iPSC产生的效率。相比之下，在稍后时间添加BMP 4减少了iPSC的产生。ID基因是BMP-SMAD信号传导的转录靶点，对iPSC的产生至关重要。BMPSMAD-ID信号轴抑制p16/INK 4A介导的细胞衰老，这是重编程的主要障碍。使用携带ACVR 1 R206 H突变的患者细胞的这些结果揭示了细胞信号传导和基因表达在重编程过程中如何变化。
Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). In normal fibroblasts, the efficiency of iPSC generation was enhanced by transducing mutant ACVR1 (617G > A) or SMAD1 or adding BMP4 protein at early times during the reprogramming. In contrast, adding BMP4 at later times decreased iPSC generation. ID genes, transcriptional targets of BMP-SMAD signaling, were critical for iPSC generation. The BMPSMAD-ID signaling axis suppressed p16/INK4A-mediated cell senescence, a major barrier to reprogramming. These results using patient cells carrying the ACVR1 R206H mutation reveal how cellular signaling and gene expression change during the reprogramming processes.