Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Germany, and German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Germany.
Address correspondence to: Thomas Eschenhagen, Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Phone: 49.40.74105.2180; Email: firstname.lastname@example.org.
First published April 16, 2018 - More info
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.
Xing Fu, Hadi Khalil, Onur Kanisicak, Justin G. Boyer, Ronald J. Vagnozzi, Bryan D. Maliken, Michelle A. Sargent, Vikram Prasad, Iñigo Valiente-Alandi, Burns C. Blaxall, Jeffery D. Molkentin
The identity and function of the fibroblast, a highly prevalent cell type in the heart, have remained poorly defined. Recent faithful genetic lineage–tracing studies revealed that during development, the cardiac fibroblasts are derived from the epicardium and the endothelium, whereas in the adult heart, they constitute the cardiac injury–responsive resident fibroblast. In the current issue of the JCI, Molkentin and colleagues decipher the time course and mechanism of the fibroblast in response to myocardial infarction (MI). The model they propose is surprisingly simple and clear. It consists of three major phases. First, fibroblasts in the ischemic area die. Second, surrounding fibroblasts proliferate and migrate into the spaces created by dying cardiomyocytes over a few days. The new fibroblasts in the scar are activated and adopt a smooth muscle actin– and periostin-positive “myofibroblast” phenotype, which appears to last as long as the scar is not mature (~10 days after MI). In the third phase, initially proliferating myofibroblasts lose smooth muscle actin expression and convert to a nonproliferating, matrix-producing phenotype with a newly acquired tendon gene signature. Interestingly, this state appears to differ from that of quiescent fibroblasts in the uninjured heart, as it is resistant to proliferative stimuli. These cells are therefore termed “matrifibrocytes,” a novel category whose study will certainly further advance the field.
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