Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart

Abstract

Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.

PDGFRα signaling in cardiac fibroblasts modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair

“…were PDGFRα bright αSMA -, as expected of resting fibroblasts. Post-MI, the infarct region contained abundant, large, tdTomato + PDGFRα dim αSMA high cells, findings consistent with recent fibroblast lineage tracing studies [34][35][36] .…”

High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy

“…Thbs4 more closely resemble matrifibrocytes that reside in a mature scar after MI[15]. Although expression of key matrifibrocyte marker genes-Comp, Sfrp2 or Wisp2-were not highly enriched in cells defined as Fibroblast-Cilp and Fibroblast-Thbs4 in this study, the functional inferences made of these cell populations are comparable.…”

“…Finally, in accordance with transcriptomic analyses, we confirmed that neither Fibroblast-Cilp nor Fibroblast-Thbs4 correspond to ACTA2 + myofibroblasts ( Figure 4G and H) using mice from two independent mouse colonies. These findings suggest that Fibroblast-Cilp and Fibroblast-Thbs4 may be transcriptionally similar to the matrifibrocyte, a specialized fibroblast state found in the mature scar after MI [15]. While Fibroblast-Cilp/Thbs4 had some expression of the matrifibrocyte markers Comp, Sfrp2, and…”

“…Wisp2 [6,15], these genes are less specific for Fibroblast-Cilp and Fibroblast-Thbs4 than Cilp, Ddah1, or Thbs4 (Online Figure 11).…”

Single-cell RNA-seq analysis reveals the crucial role of Collagen Triplex Helix Repeat Containing 1 (CTHRC1) cardiac fibroblasts for ventricular remodeling after myocardial infarction

“…A recent study has defined the CF response after MI using three different mouse models of cell lineage tracing 31 . The results of this study, based on stage specific transcriptomics, suggest a model of CF kinetics that includes the initial proliferation followed by activation and migration of CF and eventually the conversion of these activated CF into non-proliferating, matrixproducing fibroblast named "matrifibrocytes" 31 . IRCF show a similar transcriptional signature and anatomical location into the fibrotic scar to "matrifibrocytes" ( Fig.…”