Journal
CELL STEM CELL
Volume 21, Issue 6, Pages 791-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2017.10.013
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Funding
- ERC [ROADTOIPS 261075, BRAINCELL 261063, iN-Brain 309712]
- BBSRC [BB/L023474/1]
- Anne Rowling Regenerative Neurology Clinic
- Swedish Research Council (grant STARGET) [521-2012-5624, 521-2013-3347]
- Wellcome Trust [WT098051]
- Darwin Trust scholarship from the University of Edinburgh
- CMVM scholarship from the University of Edinburgh
- Principal's Career Development scholarship from the University of Edinburgh
- BBSRC (EASTBIO doctoral training partnership)
- Juan de la Cierva postdoctoral fellowship (MINECO) [FJCI-2014-22946]
- EMBO long-term fellowship [ALTF 1143-2015]
- Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa
- CERCA Program Generalitat de Catalunya
- BBSRC [BB/L023474/1] Funding Source: UKRI
- MRC [MR/N008715/1, MR/L012766/1, MR/K017047/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L023474/1] Funding Source: researchfish
- Medical Research Council [MR/K017047/1, MR/L012766/1, 1481829, MR/N008715/1] Funding Source: researchfish
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Reprogramming of cellular identity using exogenous expression of transcription factors (TFs) is a powerful and exciting tool for tissue engineering, disease modeling, and regenerative medicine. However, generation of desired cell types using this approach is often plagued by inefficiency, slow conversion, and an inability to produce mature functional cells. Here, we show that expression of constitutively active SMAD2/3 significantly improves the efficiency of induced pluripotent stem cell (iPSC) generation by the Yamanaka factors. Mechanistically, SMAD3 interacts with reprogramming factors and co-activators and co-occupies OCT4 target loci during reprogramming. Unexpectedly, active SMAD2/3 also markedly enhances three other TF-mediated direct reprogramming conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons, highlighting broad and general roles for SMAD2/3 as cell-reprogramming potentiators. Our results suggest that co-expression of active SMAD2/3 could enhance multiple types of TF-based cell identity conversion and therefore be a powerful tool for cellular engineering.
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