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A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype

Cardiac fibrosis is associated with activation of cardiac fibroblasts (CFs), a pathological, phenotypic transition that is widely believed to be irreversible in the late stages of disease development. Sensing of a stiffened mechanical environment through regulation of integrin-based adhesion plaques...

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Autores principales: Niu, Lele, Cheng, Bo, Huang, Guoyou, Nan, Kai, Han, Shuang, Ren, Hui, Liu, Na, Li, Yan, Genin, Guy M., Xu, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448780/
https://www.ncbi.nlm.nih.gov/pubmed/36068215
http://dx.doi.org/10.1038/s41421-022-00427-w
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author Niu, Lele
Cheng, Bo
Huang, Guoyou
Nan, Kai
Han, Shuang
Ren, Hui
Liu, Na
Li, Yan
Genin, Guy M.
Xu, Feng
author_facet Niu, Lele
Cheng, Bo
Huang, Guoyou
Nan, Kai
Han, Shuang
Ren, Hui
Liu, Na
Li, Yan
Genin, Guy M.
Xu, Feng
author_sort Niu, Lele
collection PubMed
description Cardiac fibrosis is associated with activation of cardiac fibroblasts (CFs), a pathological, phenotypic transition that is widely believed to be irreversible in the late stages of disease development. Sensing of a stiffened mechanical environment through regulation of integrin-based adhesion plaques and activation of the Piezo1 mechanosensitive ion channel is known to factor into this transition. Here, using integrated in vitro and in silico models, we discovered a mutually reinforcing, mechanical positive feedback loop between integrin β1 and Piezo1 activation that forms a bistable switch. The bistable switch is initiated by perturbations in matrix elastic modulus that amplify to trigger downstream signaling involving Ca(2+) and YAP that, recursively, leads fibroblasts to further stiffen their environment. By simultaneously interfering with the newly identified mechanical positive feedback loop and modulating matrix elastic modulus, we reversed markers of phenotypical transition of CF, suggesting new therapeutic targets for fibrotic disease.
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spelling pubmed-94487802022-09-08 A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype Niu, Lele Cheng, Bo Huang, Guoyou Nan, Kai Han, Shuang Ren, Hui Liu, Na Li, Yan Genin, Guy M. Xu, Feng Cell Discov Article Cardiac fibrosis is associated with activation of cardiac fibroblasts (CFs), a pathological, phenotypic transition that is widely believed to be irreversible in the late stages of disease development. Sensing of a stiffened mechanical environment through regulation of integrin-based adhesion plaques and activation of the Piezo1 mechanosensitive ion channel is known to factor into this transition. Here, using integrated in vitro and in silico models, we discovered a mutually reinforcing, mechanical positive feedback loop between integrin β1 and Piezo1 activation that forms a bistable switch. The bistable switch is initiated by perturbations in matrix elastic modulus that amplify to trigger downstream signaling involving Ca(2+) and YAP that, recursively, leads fibroblasts to further stiffen their environment. By simultaneously interfering with the newly identified mechanical positive feedback loop and modulating matrix elastic modulus, we reversed markers of phenotypical transition of CF, suggesting new therapeutic targets for fibrotic disease. Springer Nature Singapore 2022-09-06 /pmc/articles/PMC9448780/ /pubmed/36068215 http://dx.doi.org/10.1038/s41421-022-00427-w Text en © The Author(s) 2022 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Niu, Lele
Cheng, Bo
Huang, Guoyou
Nan, Kai
Han, Shuang
Ren, Hui
Liu, Na
Li, Yan
Genin, Guy M.
Xu, Feng
A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
title A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
title_full A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
title_fullStr A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
title_full_unstemmed A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
title_short A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
title_sort positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448780/
https://www.ncbi.nlm.nih.gov/pubmed/36068215
http://dx.doi.org/10.1038/s41421-022-00427-w
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