The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation
Background A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.019904 |
| _version_ | 1797936091968307200 |
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| author | Nicholas W. Chavkin Soichi Sano Ying Wang Kosei Oshima Hayato Ogawa Keita Horitani Miho Sano Susan MacLauchlan Anders Nelson Karishma Setia Tanvi Vippa Yosuke Watanabe Jeffrey J. Saucerman Karen K. Hirschi Noyan Gokce Kenneth Walsh |
| author_facet | Nicholas W. Chavkin Soichi Sano Ying Wang Kosei Oshima Hayato Ogawa Keita Horitani Miho Sano Susan MacLauchlan Anders Nelson Karishma Setia Tanvi Vippa Yosuke Watanabe Jeffrey J. Saucerman Karen K. Hirschi Noyan Gokce Kenneth Walsh |
| author_sort | Nicholas W. Chavkin |
| collection | DOAJ |
| description | Background A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase–like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload. |
| first_indexed | 2024-04-10T18:24:20Z |
| format | Article |
| id | doaj.art-3e860529ade5404993cc7ef1c0e568cb |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T18:24:20Z |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-3e860529ade5404993cc7ef1c0e568cb2023-02-02T06:18:05ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802021-07-01101310.1161/JAHA.120.019904The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast DifferentiationNicholas W. Chavkin0Soichi Sano1Ying Wang2Kosei Oshima3Hayato Ogawa4Keita Horitani5Miho Sano6Susan MacLauchlan7Anders Nelson8Karishma Setia9Tanvi Vippa10Yosuke Watanabe11Jeffrey J. Saucerman12Karen K. Hirschi13Noyan Gokce14Kenneth Walsh15Cardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VAMolecular Cardiology/Whitaker Cardiovascular Institute Boston University School of Medicine Boston MACardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VAMolecular Cardiology/Whitaker Cardiovascular Institute Boston University School of Medicine Boston MACardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VAVascular Biology/Whitaker Cardiovascular Institute Boston University School of Medicine Boston MACardiovascular Research Center School of Medicine University of Virginia Charlottesville VACardiovascular Research Center School of Medicine University of Virginia Charlottesville VABoston University School of Medicine Boston MACardiovascular Research Center School of Medicine University of Virginia Charlottesville VABackground A hallmark of heart failure is cardiac fibrosis, which results from the injury‐induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase–like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.https://www.ahajournals.org/doi/10.1161/JAHA.120.019904fibroblastsfibrosisheart failureinflammationmyocardial inflammation |
| spellingShingle | Nicholas W. Chavkin Soichi Sano Ying Wang Kosei Oshima Hayato Ogawa Keita Horitani Miho Sano Susan MacLauchlan Anders Nelson Karishma Setia Tanvi Vippa Yosuke Watanabe Jeffrey J. Saucerman Karen K. Hirschi Noyan Gokce Kenneth Walsh The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease fibroblasts fibrosis heart failure inflammation myocardial inflammation |
| title | The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation |
| title_full | The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation |
| title_fullStr | The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation |
| title_full_unstemmed | The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation |
| title_short | The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation |
| title_sort | cell surface receptors ror1 2 control cardiac myofibroblast differentiation |
| topic | fibroblasts fibrosis heart failure inflammation myocardial inflammation |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.019904 |
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