Abstract
Fibroblast (Fb) differentiation and interstitial fibrosis contribute to cardiac remodeling and loss of function after myocardial infarction (MI). We investigated regional presence and regulation of fibrosis in a pig MI model. In vivo analysis of regional function and perfusion defined three regions: the scar, the myocardium adjacent to the scar (MIadjacent, reduced function, reduced perfusion reserve), and the remote myocardium (MIremote, minimal functional deficit, maintained perfusion). Interstitial and perivascular fibrosis, and increase of collagen type I, was only observed in the MIadjacent. Fb activated protein-alpha (FAP-α) was enriched in MIadjacent compared to MIremote. TGF-β1, which triggers Fb differentiation, was upregulated in both MIadjacent and MIremote, whereas lysyl oxidase, a regulator of collagen cross-linking, and the proteoglycans decorin and biglycan were only increased in the MIadjacent. Fb isolated and cultured for 4 days had myoFb characteristics with little difference between MIremote and MIadjacent, although RNA sequencing revealed differences in gene expression profiles. Fbs from all regions maintained proliferative capacity, and induced contraction of 3-D collagen matrices but scar myoFb was more effective. These data suggest that after MI, signaling through TGF-β1, possibly related to increased mechanical load, drives Fb activation throughout the left ventricle while regional signaling determines further maturation and extracellular matrix remodeling after MI.
Highlights
Fibroblasts (Fb) belong to the most abundant cell type in the heart next to myocytes and endothelial cells[1]
Ultra-structural evaluation by transmission electron microscopy suggests the presence of cross-linked collagen type I fibers enveloping the sarcolemma of the cardiac myocytes (Supplemental Fig.1D)
Quantification of interstitial fibrosis is shown in Fig. 1B. mRNA levels confirmed the histological observations showing a 3-fold increase of collagen type I in MIadjacent when compared to SHAM (Fig. 1C), whereas collagen type III in myocardial infarction (MI) revealed no differences (Fig. 1C)
Summary
Fibroblasts (Fb) belong to the most abundant cell type in the heart next to myocytes and endothelial cells[1]. Further differentiation into myofibroblasts (MyoFb) is associated with the development of a mature α-SMA stress fiber network At this stage, MyoFb have acquired the capacity to remodel the ECM by exerting high intracellular force via activated integrins[13] and cadherin receptor proteins[14]. MyoFb have acquired the capacity to remodel the ECM by exerting high intracellular force via activated integrins[13] and cadherin receptor proteins[14] They produce high levels of pro-collagen fibrils, which after secretion are cross-linked by lysyl oxidase (LOX) into mature collagen fibers[15, 16]. Region-specific fibroblast phenotypes in the scar tissue and in non-infarcted myocardium and their functional role during post-MI remodeling are less studied. We analyzed interstitial fibrosis in matched tissue samples and compared activation of signaling pathways
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