Excess TGF-β1 Drives Cardiac Mesenchymal Stromal Cells to a Pro-Fibrotic Commitment in Arrhythmogenic Cardiomyopathy

Abstract

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-β1 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-β1 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-β1.

Compromised Biomechanical Properties, Cell–Cell Adhesion and Nanotubes Communication in Cardiac Fibroblasts Carrying the Lamin A/C D192G Mutation

“…According to our results, the mutation of the lamina cortex could induce the decrease of extracellular communication by TNT during ACM pathology. Lack of communication from fibroblasts in cardiac tissue could bring fibrofatty infiltration in cardiomyocytes with tissue fibrosis [63][64][65]. Several reports illustrated the function of fibroblasts in the ECM production and their role in fibrosis and adipogenesis [63][64][65][66].…”

“…Lack of communication from fibroblasts in cardiac tissue could bring fibrofatty infiltration in cardiomyocytes with tissue fibrosis [63][64][65]. Several reports illustrated the function of fibroblasts in the ECM production and their role in fibrosis and adipogenesis [63][64][65][66]. Cells in the cardiac tissue secrete fibrogenic mediators and matricellular proteins that bind to the fibroblast surface receptors.…”

Modeling Cardiomyopathies in a Dish: State-of-the-Art and Novel Perspectives on hiPSC-Derived Cardiomyocytes Maturation

“…Cardiac fibroblasts and endothelial cells, for instance, can mimic biophysical and biochemical cues as a result of their ability to create the ECM and angiogenesis, respectively [ 68 , 69 ]. Nevertheless, 2D cultures cannot fully recapitulate the microenvironment, three-dimensional alignment, and the complex architectural network that occurs in an in vivo system.…”

“…Different readouts are to be tested in different forms of cardiomyopathies: (i) electrophysiology and fields potentials can be monitored both in channelopathies and in structural cardiomyopathies and are essential to model arrhythmic dysfunction [ 92 ]; (ii) marker for altered pathways are readouts needed to understand the pathogenic mechanisms in every form of cardiomyopathies [ 93 , 94 ]; (iii) testing calcium handling dysregulation is important in channelopathies, as CPVT, but also in structural cardiomyopathies as Dilated Cardiomyopathy (DCM) and ARVC [ 95 , 96 ]; (iv) motion analysis and force measurements need to be tested mainly in the structural cardiomyopathies [ 97 ]; (v) similarly, the evaluation of ECM deposition is a common feature of pro-fibrotic tissue remodeling [ 69 ].…”

Sudden Unexpected Death Associated with Arrhythmogenic Cardiomyopathy: Study of the Cardiac Conduction System

“…Cardiac mesenchymal stromal cells (C-MSC) are the most abun-dant cells in the heart, with propensity to differentiate into several cell types, including adipocytes; they contribute to the adipogenic substitution of cardiomyocytes observed in ACM [42]. C-MSC are a source of myofibroblasts and participate in ACM fibrotic remodeling, being highly responsive to ACM-characteristic excess of transforming growth factor-β (TGF-β) [43].…”