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

Autor:	Ruetz T; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Pfisterer U; Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden., Di Stefano B; Centre for Genomic Regulation, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain., Ashmore J; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Beniazza M; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Tian TV; Centre for Genomic Regulation, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain., Kaemena DF; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Tosti L; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Tan W; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Manning JR; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Chantzoura E; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Ottosson DR; Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden., Collombet S; Institut de Biologie de l'Ecole Normale Supérieure, CNRS UMR8197, INSERM U1024, 75005 Paris, France., Johnsson A; Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, SE-171 77 Stockholm, Sweden., Cohen E; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK., Yusa K; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK., Linnarsson S; Laboratory for Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, SE-171 77 Stockholm, Sweden., Graf T; Centre for Genomic Regulation, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; The Barcelona Institute of Science and Technology, Carrer del Comte d'Urgell 187, Building 12 (BIST), 08036 Barcelona, Spain., Parmar M; Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden., Kaji K; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK. Electronic address: keisuke.kaji@ed.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2017 Dec 07; Vol. 21 (6), pp. 791-805.e9. Date of Electronic Publication: 2017 Nov 22.
DOI:	10.1016/j.stem.2017.10.013
Abstrakt:	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. (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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