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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 10

Changes in gene-expression states in the cardiac fibroblast after infarction injury.

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Changes in gene-expression states in the cardiac fibroblast after infarc...
(A) Heatmap of selected gene-expression categories and individual genes from Tcf21 lineage–traced fibroblasts isolated from the uninjured heart or the infarct area of hearts 3 days, 7 days, 2 weeks, and 4 weeks after MI (assayed with Affymetrix microarrays). (B–I) Bar graphs show mRNA expression levels of selected cell proliferation–related genes (B), cell migration–related genes (C), cytoskeleton-related genes (D), ECM protein genes (E), ECM modification genes (F), bone and cartilage–related genes (G), apoptosis inhibitor genes (H), and fibroblast marker genes (I) in the different sample groups. Data were normalized to quiescent Tcf21 lineage–traced fibroblasts isolated from uninjured hearts. n = 3 (uninjured, 3 d MI, 7 d MI, and 4 wk MI), n = 2 (2 wk MI). Different letters (a, b, c, d, e) above the bars indicate significant differences (P < 0.05) by 1-way ANOVA and Tukey’s post hoc analysis between Tcf21 lineage–traced fibroblasts isolated at different time points in each panel. Bars denoted by the same letter indicate lack of significant difference within that panel, while all bars that have different letters are significantly different from each other.

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

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