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

Abstract:

: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.

authors

Hayashi Y,Hsiao EC,Sami S,Lancero M,Schlieve CR,Nguyen T,Yano K,Nagahashi A,Ikeya M,Matsumoto Y,Nishimura K,Fukuda A,Hisatake K,Tomoda K,Asaka I,Toguchida J,Conklin BR,Yamanaka S

doi

10.1073/pnas.1603668113

subject

Has Abstract

pub_date

2016-11-15 00:00:00

pages

13057-13062

issue

46

eissn

0027-8424

issn

1091-6490

pii

1603668113

journal_volume

113

pub_type

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