Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1784784142174519296 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9448780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Nature Singapore |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT niulele apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT chengbo apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT huangguoyou apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT nankai apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT hanshuang apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT renhui apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT liuna apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT liyan apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT geninguym apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT xufeng apositivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT niulele positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT chengbo positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT huangguoyou positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT nankai positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT hanshuang positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT renhui positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT liuna positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT liyan positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT geninguym positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype AT xufeng positivemechanobiologicalfeedbackloopcontrolsbistableswitchingofcardiacfibroblastphenotype |