Consequences of PDGFRα+ fibroblast reduction in adult murine hearts
Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poor...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69854 |
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| author | Jill T Kuwabara Akitoshi Hara Sumit Bhutada Greg S Gojanovich Jasmine Chen Kanani Hokutan Vikram Shettigar Anson Y Lee Lydia P DeAngelo Jack R Heckl Julia R Jahansooz Dillon K Tacdol Mark T Ziolo Suneel S Apte Michelle D Tallquist |
| author_facet | Jill T Kuwabara Akitoshi Hara Sumit Bhutada Greg S Gojanovich Jasmine Chen Kanani Hokutan Vikram Shettigar Anson Y Lee Lydia P DeAngelo Jack R Heckl Julia R Jahansooz Dillon K Tacdol Mark T Ziolo Suneel S Apte Michelle D Tallquist |
| author_sort | Jill T Kuwabara |
| collection | DOAJ |
| description | Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE-infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with a potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease. |
| first_indexed | 2024-04-11T09:31:13Z |
| format | Article |
| id | doaj.art-59bd1881150d4f2a8b06cd161b15c44e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:31:13Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-59bd1881150d4f2a8b06cd161b15c44e2022-12-22T04:31:52ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.69854Consequences of PDGFRα+ fibroblast reduction in adult murine heartsJill T Kuwabara0Akitoshi Hara1Sumit Bhutada2https://orcid.org/0000-0002-5274-5122Greg S Gojanovich3Jasmine Chen4Kanani Hokutan5Vikram Shettigar6Anson Y Lee7Lydia P DeAngelo8https://orcid.org/0000-0002-0549-325XJack R Heckl9Julia R Jahansooz10Dillon K Tacdol11Mark T Ziolo12Suneel S Apte13https://orcid.org/0000-0001-8441-1226Michelle D Tallquist14https://orcid.org/0000-0002-1383-144XCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United States; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesDepartment of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United States; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesDorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United States; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesDorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, United StatesDepartment of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United StatesCenter for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United StatesFibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE-infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with a potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.https://elifesciences.org/articles/69854fibroblastextracellular matrixhomeostasis |
| spellingShingle | Jill T Kuwabara Akitoshi Hara Sumit Bhutada Greg S Gojanovich Jasmine Chen Kanani Hokutan Vikram Shettigar Anson Y Lee Lydia P DeAngelo Jack R Heckl Julia R Jahansooz Dillon K Tacdol Mark T Ziolo Suneel S Apte Michelle D Tallquist Consequences of PDGFRα+ fibroblast reduction in adult murine hearts eLife fibroblast extracellular matrix homeostasis |
| title | Consequences of PDGFRα+ fibroblast reduction in adult murine hearts |
| title_full | Consequences of PDGFRα+ fibroblast reduction in adult murine hearts |
| title_fullStr | Consequences of PDGFRα+ fibroblast reduction in adult murine hearts |
| title_full_unstemmed | Consequences of PDGFRα+ fibroblast reduction in adult murine hearts |
| title_short | Consequences of PDGFRα+ fibroblast reduction in adult murine hearts |
| title_sort | consequences of pdgfrα fibroblast reduction in adult murine hearts |
| topic | fibroblast extracellular matrix homeostasis |
| url | https://elifesciences.org/articles/69854 |
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