Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 46, Pages 13057-13062Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1603668113
Keywords
reprogramming; pluripotency; BMP; senescence; FOP
Categories
Funding
- NIH [R01 HL60664-07, K08 AR056299-02]
- California Institute of Regenerative Medicine/Gladstone Institutes California Institute for Regenerative Medicine (CIRM) Fellowship [T2-00003]
- University of California, San Francisco (UCSF) Department of Medicine
- March of Dimes Basil O'Connor Starter Grant [5-FY12-167]
- Duke-NUS Graduate Medical School Singapore Third-Year Research Program
- Japan Ministry of Education, Culture, Sports, Science, and Technology
- Leading Project for Realization of Regenerative Medicine
- Uehara Memorial Foundation
- USCF's Program for Breakthrough Biomedical Research
- Kyoto University Grants
- Japan Society for the Promotion of Science (JSPS)
- Ministry of Education, Culture, Sports, Science and Technology-Japan (MEXT)
- Program for Promotion of Fundamental Studies in Health Sciences of National Institute of Biomedical Innovation (NIBIO) (Japan)
- L.K. Whittier Foundation
- Roddenberry Foundation
- National Center for Research Resources Grant [RR18928]
- Grants-in-Aid for Scientific Research [16K08610] Funding Source: KAKEN
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available