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

Ruetz, Tyson; Pfisterer, Ulrich LU ; Di Stefano, Bruno; Ashmore, James; Beniazza, Meryam; Tian, Tian V.; Kaemena, Daniel F.; Tosti, Luca; Tan, Wenfang and Manning, Jonathan R., et al. (2017) In Cell Stem Cell p.9-805
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... (More)

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. 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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published
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keywords
Direct reprogramming, Induced neuron, IPSCs, Reprogramming, Smad2, Smad3, Transdifferentiation
in
Cell Stem Cell
pages
9 - 805
publisher
Cell Press
external identifiers
  • scopus:85034626659
  • wos:000417729700014
ISSN
1934-5909
DOI
10.1016/j.stem.2017.10.013
language
English
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yes
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2e301317-87b3-4be3-a194-db85a6dd3f5c
date added to LUP
2017-12-11 13:25:38
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2018-04-15 04:49:11
@article{2e301317-87b3-4be3-a194-db85a6dd3f5c,
  abstract     = {<p>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. 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.</p>},
  author       = {Ruetz, Tyson and Pfisterer, Ulrich and Di Stefano, Bruno and Ashmore, James and Beniazza, Meryam and Tian, Tian V. and Kaemena, Daniel F. and Tosti, Luca and Tan, Wenfang and Manning, Jonathan R. and Chantzoura, Eleni and Ottosson, Daniella Rylander and Collombet, Samuel and Johnsson, Anna and Cohen, Erez and Yusa, Kosuke and Linnarsson, Sten and Graf, Thomas and Parmar, Malin and Kaji, Keisuke},
  issn         = {1934-5909},
  keyword      = {Direct reprogramming,Induced neuron,IPSCs,Reprogramming,Smad2,Smad3,Transdifferentiation},
  language     = {eng},
  pages        = {9--805},
  publisher    = {Cell Press},
  series       = {Cell Stem Cell},
  title        = {Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming},
  url          = {http://dx.doi.org/10.1016/j.stem.2017.10.013},
  year         = {2017},
}