期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/ijms22052673
关键词
arrhythmogenic cardiomyopathy; cardiac-mesenchymal stromal cells; fibrosis; TGF-β 1; cardiac remodeling
资金
- Transnational Research Projects on Cardiovascular Diseases [ACM-HF JTC2016_FP-40-021]
- Italian Ministry of Health [RC2019 EF5C ID:2754330]
This study found that fibrotic markers are increased in cardiac biopsies of ACM patients compared to healthy controls, along with significantly higher levels of circulating TGF-beta1 in the ACM cohort. While this difference is not evident in isolated C-MSC, ACM C-MSC are more responsive to TGF-beta1 treatment, indicating their involvement in ACM fibrotic remodeling.
Arrhythmogenic Cardiomyopathy (ACM) is characterized by the replacement of the myocardium with fibrotic or fibro-fatty tissue and inflammatory infiltrates in the heart. To date, while ACM adipogenesis is a well-investigated differentiation program, ACM-related fibrosis remains a scientific gap of knowledge. In this study, we analyze the fibrotic process occurring during ACM pathogenesis focusing on the role of cardiac mesenchymal stromal cells (C-MSC) as a source of myofibroblasts. We performed the ex vivo studies on plasma and right ventricular endomyocardial bioptic samples collected from ACM patients and healthy control donors (HC). In vitro studies were performed on C-MSC isolated from endomyocardial biopsies of both groups. Our results revealed that circulating TGF-beta 1 levels are significantly higher in the ACM cohort than in HC. Accordingly, fibrotic markers are increased in ACM patient-derived cardiac biopsies compared to HC ones. This difference is not evident in isolated C-MSC. Nevertheless, ACM C-MSC are more responsive than HC ones to TGF-beta 1 treatment, in terms of pro-fibrotic differentiation and higher activation of the SMAD2/3 signaling pathway. These results provide the novel evidence that C-MSC are a source of myofibroblasts and participate in ACM fibrotic remodeling, being highly responsive to ACM-characteristic excess TGF-beta 1.
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