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

TLDR

Fibroblasts dynamically differentiate to mediate wound healing and long‑term remodeling, replacing cardiomyocytes with extracellular matrix proteins after myocardial infarction. The study aimed to phenotypically classify resident cardiac fibroblast dynamics during myocardial infarction and scar formation using three lineage‑tracing mouse models and stage‑specific gene profiling. Using these lineage‑tracing models and stage‑specific gene profiling, the authors tracked fibroblast phenotypes over time. Fibroblasts proliferated maximally 2–4 days post‑infarction, then differentiated into myofibroblasts that produced ECM and α‑actin until 7–10 days when they ceased proliferation and α‑actin expression, after which the same lineage‑traced cells persisted as matrifibrocytes with specialized ECM and tendon gene expression that support mature scar, a phenotype also observed in human hearts.

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.