Constitutively active Smad2/3 are broad scope potentiators of transcription factor-mediated cellular reprogramming

Tyson Ruetz, Ulrich Pfisterer, Bruno Di Stefano, James Ashmore, Meryam Beniazza, Tian V. Tian, Daniel F. Kaemena, Luca Tosti, Wenfang Tan, Jonathan R. Manning, Eleni Chantzoura, Daniella Rylander Ottosson, Samuel Collombet, Anna Johnsson, Erez Cohen, Kosuke Yusa, Sten Linnarsson, Thomas Graf, Malin Parmar, Keisuke Kaji

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)791-805.e9
Number of pages24
JournalCell Stem Cell
Volume21
Issue number6
Early online date22 Nov 2017
DOIs
Publication statusPublished - 7 Dec 2017

Keywords

  • Journal Article

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