IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling
Year: 2023
Type: article
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.
Source: Communications Biology
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: Yale University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: National Metabolomics Data Repository - nextgen Metabolomics Workbench, CardioPulmonary Vascular Biology COBRE, G2180798817, Aspergillus fumigatus infection and fibrosis, G338578137, Biomedical Data Commons Workbench (BDCW), Molecular mechanism of hypertrophic cardiomyopathy in populations of South Asian descendants, Myoarchitectural Basis of Heart Failure, Regulators of extracellular matrix production during cardiac development and disease, IGF-2R is a new therapeutic target for cardiac ischemia-reperfusion injury, Advance Clinical and Translational Research (Advance-CTR), Understanding Cardiovascular Disease Mechanisms, Fast myosin binding protein-C and cardiac contractility in heart failure, G966013960
OpenAlex ID: W4389001893