BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence

Y Hayashi, EC Hsiao, S Sami… - Proceedings of the …, 2016 - National Acad Sciences
Y Hayashi, EC Hsiao, S Sami, M Lancero, CR Schlieve, T Nguyen, K Yano, A Nagahashi…
Proceedings of the National Academy of Sciences, 2016National Acad Sciences
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 …
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 BMP-SMAD-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.
National Acad Sciences