Preferential myofibroblast differentiation of cardiac mesenchymal progenitor cells in the presence of atrial fibrillation

Abstract

Atrial fibrillation (AF) is characterized by electrical, contractile, and structural remodeling mediated by interstitial fibrosis. It has been shown that human cardiac mesenchymal progenitor cells (CMPCs) can be differentiated into endothelial, smooth muscle, and fibroblast cells. Here, we have investigated, for the first time, the contribution of CMPCs in the fibrotic process occurring in AF. As expected, right auricolae samples displayed significantly higher fibrosis in AF vs control (CTR) patients. In tissue samples of AF patients only, double staining for c-kit and the myofibroblast marker α-smooth muscle actin (α-SMA) was detected. The number of c-kit-positive CMPC was higher in atrial subepicardial regions of CTR than AF cells. AF-derived CMPC (AF-CMPC) and CTR-derived CMPC (Ctr-CMPC) were phenotypically similar, except for CD90 and c-kit, which were significantly more present in AF and CTR cells, respectively. Moreover, AF showed a lower rate of population doubling and fold enrichment vs Ctr-CMPC. When exogenously challenged with the profibrotic transforming growth factor-β1 (TGF-β1), AF-CMPC showed a significantly higher nuclear translocation of SMAD2 than Ctr-CMPC. In addition, TGF-β1 treatment induced the upregulation of COL1A1 and COL1A2 in AF-CMPC only. Further, both a marked production of soluble collagen and α-SMA upregulation have been observed in AF-CMPC only. Finally, electrophysiological studies showed that the inwardly rectifying potassium current (I) was evenly present in AF- and Ctr-CMPC in basal conditions and similarly disappeared after TGF-β1 exposure. All together, these data suggest that AF steers the resident atrial CMPC compartment toward an electrically inert profibrotic phenotype.

Integrin ανβ5 in vitro inhibition limits pro-fibrotic response in cardiac fibroblasts of spontaneously hypertensive rats

“…Moreover, MyoFB contraction has been shown to directly activate latent TGF-β1, stored in the ECM, by integrin-mediated binding [13, 40]. In fact, it has been extensively reported that fibroblasts, in which α-SMA expression is quite low, are less efficient in the TGF-β1 activation when compared with α-SMA + MyoFB [3, 40]. In light of all these findings, it can be speculated that the hypertensive stimulus, fostered by TGF-β1 treatment, is able to push CF into a pro-fibrotic state, characterized by the up-regulation of TGF-β1/SMAD signaling leading to CF differentiation into MyoFB.…”

“…In the last 20 years, the transforming growth factor-β1 (TGF-β1) has emerged as a crucial mediator of the local cardiac remodelling, not only in hypertensive pathological scenario [2], but also in other cardiac disease [3]. In particular, active TGF-β1 enhances the differentiation of fibroblasts into contractile myofibroblasts (MyoFB), by promoting the expression of α-smooth muscle actin (α-SMA) [4, 5], and the secretion of detrimental pro-fibrotic collagen in extracellular matrix (ECM) [6].…”

Human Cell Modeling for Cardiovascular Diseases

“…Emerging technologies will allow in the future an increasingly precise understanding of the pathophysiology of CVDs and consequent therapeutic advancements. Arrhythmogenic Cardiomyopathy Pathogenic mechanism [8] BMCs Arrhythmogenic Cardiomyopathy Pathogenic mechanism [10] Heart failure - [11] CMs Heart failure Pathogenic mechanism [14] Hypertrophic Cardiomyopathy Drug discovery [16,17] C-MSCs Myocardial ischemia Pathogenic mechanism [24] Arrhythmogenic Cardiomyopathy Pathogenic mechanism/Involvement in disease pathogenesis [25] c-kit + C-MSCs Atrial Fibrillation Pathogenic mechanism [31] FAPs Arrhythmogenic Cardiomyopathy Involvement in disease pathogenesis [35] ECs Hypertension Pathogenic mechanism [39,43] Atherosclerosis Pathogenic mechanism/Involvement in disease pathogenesis [41] Pathogenic mechanism [42] VSMCs Hypertension Involvement in disease pathogenesis [48] Pathogenic mechanism [49] Atherosclerosis Differentiation phenotypes [46] Pathogenic mechanism/Drug discovery [47] AC 16 Hypertrophic Cardiomyopathy Drug discovery [51] Myocardial ischemia Pathogenic mechanism [52] hESC-CMs Hypertrophic Cardiomyopathy Pathogenic mechanism [64,65] hiPSC-CMs Atrial Fibrillation Pathogenic mechanism [76] Hypertrophic Cardiomyopathy Drug discovery [78] Long QT Syndrome Pathogenic mechanism/Drug discovery [79] hiPSC-ECs Hypertension Drug discovery [81] Moyamoya disease Pathogenic mechanism [82] hiPSC-SMCs Supravalvular aortic stenosis syndrome Pathogenic mechanism [83] Bicuspid Aortic Valve-related Thoracic Aortic Aneurysm Pathogenic mechanism/Drug discovery [84] VSMCs and CD14 + cells co-culture Atherosclerosis Pathogenic mechanism [88] [89] ECs and VSMCs co-culture Atherosclerosis Pathogenic mechanism [90]...…”

“…Recently, Gambini et al analyzed the differentiation properties of cardiac mesenchymal progenitor cells (CMPCs, stromal cells positive for c-kit) deriving from patients with Atrial Fibrillation (AF), in order to establish the pro-fibrotic contribution of these cells in the pathogenesis of the disease, where atrial fibrosis has a critical role. Cells were isolated from patients’ atrial appendages and AF CMPCs resulted fewer in number and less capable of expansion than controls, but with a more pronounced pro-fibrotic phenotype [ 31 ].…”

CaMKII Activity in the Inflammatory Response of Cardiac Diseases

“…In addition, TGF-β, another cardiokine that also has a physiological cardioprotective effect, if deregulated, actively participates in the pathological cardiac remodeling mediating the tissue fibrosis that follows the tissue-injury-derived inflammation acting on fibroblast activation, differentiation, and extracellular matrix protein secretion [20,21]. TGF-β1 over-expression has been associated with myocardial hypertrophy, hypertensive cardiac remodeling, several cardiomyopathies, and genetic aortic syndromes [22,23].…”