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Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells

The epicardium has emerged as a multipotent cardiovascular progenitor source with therapeutic potential for coronary smooth muscle cell, cardiac fibroblast (CF) and cardiomyocyte regeneration, owing to its fundamental role in heart development and its potential ability to initiate myocardial repair...

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Autores principales: Iyer, Dharini, Gambardella, Laure, Bernard, William G., Serrano, Felipe, Mascetti, Victoria L., Pedersen, Roger A., Talasila, Amarnath, Sinha, Sanjay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392600/
https://www.ncbi.nlm.nih.gov/pubmed/25813541
http://dx.doi.org/10.1242/dev.119271
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author Iyer, Dharini
Gambardella, Laure
Bernard, William G.
Serrano, Felipe
Mascetti, Victoria L.
Pedersen, Roger A.
Talasila, Amarnath
Sinha, Sanjay
author_facet Iyer, Dharini
Gambardella, Laure
Bernard, William G.
Serrano, Felipe
Mascetti, Victoria L.
Pedersen, Roger A.
Talasila, Amarnath
Sinha, Sanjay
author_sort Iyer, Dharini
collection PubMed
description The epicardium has emerged as a multipotent cardiovascular progenitor source with therapeutic potential for coronary smooth muscle cell, cardiac fibroblast (CF) and cardiomyocyte regeneration, owing to its fundamental role in heart development and its potential ability to initiate myocardial repair in injured adult tissues. Here, we describe a chemically defined method for generating epicardium and epicardium-derived smooth muscle cells (EPI-SMCs) and CFs from human pluripotent stem cells (HPSCs) through an intermediate lateral plate mesoderm (LM) stage. HPSCs were initially differentiated to LM in the presence of FGF2 and high levels of BMP4. The LM was robustly differentiated to an epicardial lineage by activation of WNT, BMP and retinoic acid signalling pathways. HPSC-derived epicardium displayed enhanced expression of epithelial- and epicardium-specific markers, exhibited morphological features comparable with human foetal epicardial explants and engrafted in the subepicardial space in vivo. The in vitro-derived epicardial cells underwent an epithelial-to-mesenchymal transition when treated with PDGF-BB and TGFβ1, resulting in vascular SMCs that displayed contractile ability in response to vasoconstrictors. Furthermore, the EPI-SMCs displayed low density lipoprotein uptake and effective lowering of lipoprotein levels upon treatment with statins, similar to primary human coronary artery SMCs. Cumulatively, these findings suggest that HPSC-derived epicardium and EPI-SMCs could serve as important tools for studying human cardiogenesis, and as a platform for vascular disease modelling and drug screening.
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spelling pubmed-43926002015-05-04 Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells Iyer, Dharini Gambardella, Laure Bernard, William G. Serrano, Felipe Mascetti, Victoria L. Pedersen, Roger A. Talasila, Amarnath Sinha, Sanjay Development Techniques and Resources The epicardium has emerged as a multipotent cardiovascular progenitor source with therapeutic potential for coronary smooth muscle cell, cardiac fibroblast (CF) and cardiomyocyte regeneration, owing to its fundamental role in heart development and its potential ability to initiate myocardial repair in injured adult tissues. Here, we describe a chemically defined method for generating epicardium and epicardium-derived smooth muscle cells (EPI-SMCs) and CFs from human pluripotent stem cells (HPSCs) through an intermediate lateral plate mesoderm (LM) stage. HPSCs were initially differentiated to LM in the presence of FGF2 and high levels of BMP4. The LM was robustly differentiated to an epicardial lineage by activation of WNT, BMP and retinoic acid signalling pathways. HPSC-derived epicardium displayed enhanced expression of epithelial- and epicardium-specific markers, exhibited morphological features comparable with human foetal epicardial explants and engrafted in the subepicardial space in vivo. The in vitro-derived epicardial cells underwent an epithelial-to-mesenchymal transition when treated with PDGF-BB and TGFβ1, resulting in vascular SMCs that displayed contractile ability in response to vasoconstrictors. Furthermore, the EPI-SMCs displayed low density lipoprotein uptake and effective lowering of lipoprotein levels upon treatment with statins, similar to primary human coronary artery SMCs. Cumulatively, these findings suggest that HPSC-derived epicardium and EPI-SMCs could serve as important tools for studying human cardiogenesis, and as a platform for vascular disease modelling and drug screening. The Company of Biologists 2015-04-15 /pmc/articles/PMC4392600/ /pubmed/25813541 http://dx.doi.org/10.1242/dev.119271 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Techniques and Resources
Iyer, Dharini
Gambardella, Laure
Bernard, William G.
Serrano, Felipe
Mascetti, Victoria L.
Pedersen, Roger A.
Talasila, Amarnath
Sinha, Sanjay
Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
title Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
title_full Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
title_fullStr Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
title_full_unstemmed Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
title_short Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
title_sort robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells
topic Techniques and Resources
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392600/
https://www.ncbi.nlm.nih.gov/pubmed/25813541
http://dx.doi.org/10.1242/dev.119271
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