Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming

Publication date: Available online 22 November 2017
Source:Cell Stem Cell
Author(s): 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
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.

Graphical abstract

Teaser

Ruetz et al. show that constitutively active SMAD2/3 has a surprising ability to boost the efficiency of cell reprogramming both to iPSCs and across lineages and may therefore be a general factor that can enhance transcription-factor-mediated reprogramming in a variety of contexts.


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