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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 3

Apoptosis and turnover of Tcf21 lineage–traced fibroblasts after MI.

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Apoptosis and turnover of Tcf21 lineage–traced fibroblasts after MI.
(A)...
(A) Experimental scheme of tamoxifen treatment of Tcf21MCM/+;R26EGFP mice before MI. Hearts were harvested at the indicated time points after MI for TUNEL staining. (B) Representative TUNEL staining (red) images from 3 separate hearts analyzed showing apoptotic Tcf21 lineage–traced (EGFP+) fibroblasts after MI. Nuclei are shown with DAPI (blue). The inset shows a higher magnification (×8) image of a TUNEL+ EGFP+ cell. (C) Experimental scheme of tamoxifen treatment of Tcf21MCM/+;R26EGFP mice before MI followed by 7 daily EdU injections during the first week after MI. Hearts were then harvested 4 hours and 28 days after the last EdU injection for IHC analysis. (D and E) Quantification (D) of EdU+ (white) Tcf21 lineage–traced (EGFP+) fibroblasts in the infarcted area at 4 hours and 28 days after the last injection of 7 daily EdU injections. (E) Nuclei are shown with DAPI (blue), and αSMA (red) was stained to show myofibroblast identity. Data are shown as mean ± SD (n = 3 hearts analyzed). Two-tailed t test showed no significance. For E, representative IHC images are shown from 3 separate hearts analyzed. (F) Representative IHC images from 3 separate hearts analyzed showing EdU+ (white) CD31+ endothelial cells (red) versus Tcf21 lineage–traced fibroblasts (EGFP+) in hearts before MI and within infarct region at day 4 and day 10 after MI 4 hours after a single EdU injection. (G) Representative IHC images from 3 hearts analyzed showing EdU+ (white) CD45+ leukocytes (red) versus Tcf21 lineage–traced fibroblasts (EGFP+) in hearts before MI and within infarct region at day 4 and day 10 after MI 4 hours after a single EdU injection. Scale bars: 20 μm.

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

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