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Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart
Xing Fu, … , Burns C. Blaxall, Jeffery D. Molkentin
Xing Fu, … , Burns C. Blaxall, Jeffery D. Molkentin
Published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2127-2143. https://doi.org/10.1172/JCI98215.
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Research Article Cardiology

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

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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.

Authors

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

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Figure 4

Lineage tracing of myofibroblasts in Acta2CreERT2;R26EGFP mice.

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Lineage tracing of myofibroblasts in Acta2CreERT2;R26EGFP mice.
(A) Sche...
(A) Schematic of the Acta2 BAC with a tamoxifen-regulated CreERT2 cDNA cassette inserted into exon 1, and mice containing this transgene were crossed with R26EGFP reporter mice containing a loxP site–flanked stop cassette upstream of EGFP to allow for Cre-dependent lineage tracing. (B) Experimental scheme whereby Acta2CreERT2;R26EGFP mice were given tamoxifen through daily i.p. injections from day –1 to day 4 after MI. Mice were treated with a single EdU injection at the indicated time points after MI, and hearts were harvested 4 hours afterward for IHC analysis. (C and D) Representative IHC images from 3 hearts analyzed showing αSMA protein (red) and EdU+ (white) in αSMA lineage–traced (EGFP+) fibroblasts in the infarct region after a single EdU injection at the indicated time points after MI (C) and quantification (D). Nuclei are shown with DAPI (blue). Data are shown as mean ± SD (n = 3). Scale bars: 20 μm. (E) Representative IHC images from 3 separate hearts analyzed showing αSMA lineage–traced (EGFP+) fibroblasts and expression of αSMA protein (red) in the infarct region and border zone at 7 days and 8 weeks after MI. Nuclei are shown with DAPI (blue). Scale bars: 200 μm.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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