IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling
Abstract The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts exp...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05463-0 |
| _version_ | 1797451746406039552 |
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| author | Jamila H. Siamwala Francesco S. Pagano Patrycja M. Dubielecka Malina J. Ivey Jose Pedro Guirao-Abad Alexander Zhao Sonja Chen Haley Granston Jae Yun Jeong Sharon Rounds Onur Kanisicak Sakthivel Sadayappan Richard J. Gilbert |
| author_facet | Jamila H. Siamwala Francesco S. Pagano Patrycja M. Dubielecka Malina J. Ivey Jose Pedro Guirao-Abad Alexander Zhao Sonja Chen Haley Granston Jae Yun Jeong Sharon Rounds Onur Kanisicak Sakthivel Sadayappan Richard J. Gilbert |
| author_sort | Jamila H. Siamwala |
| collection | DOAJ |
| description | Abstract The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1β increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1β also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1β induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1β induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling. |
| first_indexed | 2024-03-09T14:58:54Z |
| format | Article |
| id | doaj.art-3ca020faab514d768b5c553211c7fe60 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-09T14:58:54Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-3ca020faab514d768b5c553211c7fe602023-11-26T14:00:14ZengNature PortfolioCommunications Biology2399-36422023-11-016112110.1038/s42003-023-05463-0IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodelingJamila H. Siamwala0Francesco S. Pagano1Patrycja M. Dubielecka2Malina J. Ivey3Jose Pedro Guirao-Abad4Alexander Zhao5Sonja Chen6Haley Granston7Jae Yun Jeong8Sharon Rounds9Onur Kanisicak10Sakthivel Sadayappan11Richard J. Gilbert12Department of Molecular Pharmacology, Physiology and Biotechnology, Brown UniversityDepartment of Molecular Pharmacology, Physiology and Biotechnology, Brown UniversityDivision of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown UniversityDepartment of Pathology & Laboratory Medicine, College of Medicine, University of CincinnatiDepartment of Pathology & Laboratory Medicine, College of Medicine, University of CincinnatiDepartment of Molecular Pharmacology, Physiology and Biotechnology, Brown UniversityWarren Alpert Medical School of Brown University, Providence VA Medical CenterDepartment of Molecular Pharmacology, Physiology and Biotechnology, Brown UniversityDepartment of Molecular Pharmacology, Physiology and Biotechnology, Brown UniversityWarren Alpert Medical School of Brown University, Providence VA Medical CenterDepartment of Pathology & Laboratory Medicine, College of Medicine, University of CincinnatiHeart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, College of Medicine, University of CincinnatiOcean State Research Institute, Providence VA Medical CenterAbstract The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1β increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1β also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1β induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1β induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.https://doi.org/10.1038/s42003-023-05463-0 |
| spellingShingle | Jamila H. Siamwala Francesco S. Pagano Patrycja M. Dubielecka Malina J. Ivey Jose Pedro Guirao-Abad Alexander Zhao Sonja Chen Haley Granston Jae Yun Jeong Sharon Rounds Onur Kanisicak Sakthivel Sadayappan Richard J. Gilbert IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling Communications Biology |
| title | IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling |
| title_full | IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling |
| title_fullStr | IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling |
| title_full_unstemmed | IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling |
| title_short | IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling |
| title_sort | il 1β mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling |
| url | https://doi.org/10.1038/s42003-023-05463-0 |
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