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.
Highlights
Fibroblasts are a unique cell type of mesenchymal origin that are present in essentially all tissues and organs, where they regulate extracellular matrix (ECM) production and acute wound healing [1,2,3]
4-week-old Tcf21MCM/+;R26EGFP mice were put on tamoxifen diet for 4 weeks to label all resident fibroblasts; thereafter, the mice received an myocardial infarction (MI) surgical procedure at 9 weeks of age (Figure 1B and Supplemental Figure 1B)
The data show that 1 to 2 days after MI injury, transcription factor 21 (Tcf21) lineage–traced fibroblasts did not proliferate in the infarct region of the heart, by day 3, there was a robust induction of proliferation (Figure 1, C and E, and Supplemental Figure 1C)
Summary
Fibroblasts are a unique cell type of mesenchymal origin that are present in essentially all tissues and organs, where they regulate extracellular matrix (ECM) production and acute wound healing [1,2,3]. Tissue stretching, and cytokines such as TGF-β, fibroblasts become activated and differentiate into a cell type referred to as a myofibroblast. The heart is perhaps one of the more unique organs with respect to the fibrotic response and wound healing, as this tissue is not inherently regenerative and a stable scar must quickly form to prevent ventricular wall rupture. We used fibroblast stage-specific lineage tracing along with mechanistic analysis of MI-injured mice and mRNA expression profiling to annotate the stable differentiated states and dynamics of fibroblasts in the heart, which defines a fibroblast state referred to as the matrifibrocyte that resides within the mature scar
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