A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype
Abstract 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 adhesio...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-09-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-022-00427-w |
| _version_ | 1811273666972876800 |
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| author | Lele Niu Bo Cheng Guoyou Huang Kai Nan Shuang Han Hui Ren Na Liu Yan Li Guy M. Genin Feng Xu |
| author_facet | Lele Niu Bo Cheng Guoyou Huang Kai Nan Shuang Han Hui Ren Na Liu Yan Li Guy M. Genin Feng Xu |
| author_sort | Lele Niu |
| collection | DOAJ |
| description | Abstract 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 Ca2+ 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. |
| first_indexed | 2024-04-12T23:03:21Z |
| format | Article |
| id | doaj.art-51cd21a6bf87489aa8c87fb37ffe2363 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-12T23:03:21Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-51cd21a6bf87489aa8c87fb37ffe23632022-12-22T03:12:59ZengNature Publishing GroupCell Discovery2056-59682022-09-018111610.1038/s41421-022-00427-wA positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotypeLele Niu0Bo Cheng1Guoyou Huang2Kai Nan3Shuang Han4Hui Ren5Na Liu6Yan Li7Guy M. Genin8Feng Xu9The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong UniversityThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong UniversityDepartment of Engineering Mechanics, School of Civil Engineering, Wuhan UniversityDepartment of Orthopedics Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityBioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong UniversityBioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong UniversityDepartment of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Cardiology, Tangdu Hospital, Fourth Military Medical UniversityThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong UniversityThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong UniversityAbstract 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 Ca2+ 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.https://doi.org/10.1038/s41421-022-00427-w |
| spellingShingle | Lele Niu Bo Cheng Guoyou Huang Kai Nan Shuang Han Hui Ren Na Liu Yan Li Guy M. Genin Feng Xu A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype Cell Discovery |
| 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 |
| url | https://doi.org/10.1038/s41421-022-00427-w |
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