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

Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13057-13062. doi: 10.1073/pnas.1603668113. Epub 2016 Oct 28.


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.

Keywords: BMP; FOP; pluripotency; reprogramming; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Adolescent
  • Adult
  • Animals
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line
  • Cellular Reprogramming
  • Cellular Senescence
  • Child
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Female
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Mice, Transgenic
  • Middle Aged
  • Mutation
  • Myositis Ossificans* / genetics
  • Signal Transduction
  • Smad Proteins / metabolism*


  • Bone Morphogenetic Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Smad Proteins
  • ACVR1 protein, human
  • Activin Receptors, Type I