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Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype

Activation of cardiac fibroblasts and differentiation to myofibroblasts underlies development of pathological cardiac fibrosis, leading to arrhythmias and heart failure. Myofibroblasts are characterised by increased α-smooth muscle actin (α-SMA) fibre expression, secretion of collagens and changes i...

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Autores principales: Hall, Caitlin, Law, Jonathan P., Reyat, Jasmeet S., Cumberland, Max J., Hang, Shaun, Vo, Nguyen T. N., Raniga, Kavita, Weston, Chris J., O’Shea, Christopher, Townend, Jonathan N., Gehmlich, Katja, Ferro, Charles J., Denning, Chris, Pavlovic, Davor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372150/
https://www.ncbi.nlm.nih.gov/pubmed/37495732
http://dx.doi.org/10.1038/s41598-023-39369-y
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author Hall, Caitlin
Law, Jonathan P.
Reyat, Jasmeet S.
Cumberland, Max J.
Hang, Shaun
Vo, Nguyen T. N.
Raniga, Kavita
Weston, Chris J.
O’Shea, Christopher
Townend, Jonathan N.
Gehmlich, Katja
Ferro, Charles J.
Denning, Chris
Pavlovic, Davor
author_facet Hall, Caitlin
Law, Jonathan P.
Reyat, Jasmeet S.
Cumberland, Max J.
Hang, Shaun
Vo, Nguyen T. N.
Raniga, Kavita
Weston, Chris J.
O’Shea, Christopher
Townend, Jonathan N.
Gehmlich, Katja
Ferro, Charles J.
Denning, Chris
Pavlovic, Davor
author_sort Hall, Caitlin
collection PubMed
description Activation of cardiac fibroblasts and differentiation to myofibroblasts underlies development of pathological cardiac fibrosis, leading to arrhythmias and heart failure. Myofibroblasts are characterised by increased α-smooth muscle actin (α-SMA) fibre expression, secretion of collagens and changes in proliferation. Transforming growth factor-beta (TGF-β) and increased mechanical stress can initiate myofibroblast activation. Reversibility of the myofibroblast phenotype has been observed in murine cells but has not been explored in human cardiac fibroblasts. In this study, chronically activated adult primary human ventricular cardiac fibroblasts and human induced pluripotent stem cell derived cFbs (hiPSC-cFbs) were used to investigate the potential for reversal of the myofibroblast phenotype using either subculture on soft substrates or TGF-β receptor inhibition. Culture on softer plates (25 or 2 kPa Young’s modulus) did not alter proliferation or reduce expression of α-SMA and collagen 1. Similarly, culture of myofibroblasts in the presence of TGF-β inhibitor did not reverse myofibroblasts back to a quiescent phenotype. Chronically activated hiPSC-cFbs also showed attenuated response to TGF-β receptor inhibition and inability to reverse to quiescent fibroblast phenotype. Our data demonstrate substantial loss of TGF-β signalling plasticity as well as a loss of feedback from the surrounding mechanical environment in chronically activated human myofibroblasts.
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spelling pubmed-103721502023-07-28 Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype Hall, Caitlin Law, Jonathan P. Reyat, Jasmeet S. Cumberland, Max J. Hang, Shaun Vo, Nguyen T. N. Raniga, Kavita Weston, Chris J. O’Shea, Christopher Townend, Jonathan N. Gehmlich, Katja Ferro, Charles J. Denning, Chris Pavlovic, Davor Sci Rep Article Activation of cardiac fibroblasts and differentiation to myofibroblasts underlies development of pathological cardiac fibrosis, leading to arrhythmias and heart failure. Myofibroblasts are characterised by increased α-smooth muscle actin (α-SMA) fibre expression, secretion of collagens and changes in proliferation. Transforming growth factor-beta (TGF-β) and increased mechanical stress can initiate myofibroblast activation. Reversibility of the myofibroblast phenotype has been observed in murine cells but has not been explored in human cardiac fibroblasts. In this study, chronically activated adult primary human ventricular cardiac fibroblasts and human induced pluripotent stem cell derived cFbs (hiPSC-cFbs) were used to investigate the potential for reversal of the myofibroblast phenotype using either subculture on soft substrates or TGF-β receptor inhibition. Culture on softer plates (25 or 2 kPa Young’s modulus) did not alter proliferation or reduce expression of α-SMA and collagen 1. Similarly, culture of myofibroblasts in the presence of TGF-β inhibitor did not reverse myofibroblasts back to a quiescent phenotype. Chronically activated hiPSC-cFbs also showed attenuated response to TGF-β receptor inhibition and inability to reverse to quiescent fibroblast phenotype. Our data demonstrate substantial loss of TGF-β signalling plasticity as well as a loss of feedback from the surrounding mechanical environment in chronically activated human myofibroblasts. Nature Publishing Group UK 2023-07-26 /pmc/articles/PMC10372150/ /pubmed/37495732 http://dx.doi.org/10.1038/s41598-023-39369-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hall, Caitlin
Law, Jonathan P.
Reyat, Jasmeet S.
Cumberland, Max J.
Hang, Shaun
Vo, Nguyen T. N.
Raniga, Kavita
Weston, Chris J.
O’Shea, Christopher
Townend, Jonathan N.
Gehmlich, Katja
Ferro, Charles J.
Denning, Chris
Pavlovic, Davor
Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
title Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
title_full Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
title_fullStr Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
title_full_unstemmed Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
title_short Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
title_sort chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372150/
https://www.ncbi.nlm.nih.gov/pubmed/37495732
http://dx.doi.org/10.1038/s41598-023-39369-y
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