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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 11

Representative mouse and human heart IHC of selected proteins underlying the matrifibrocyte.

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Representative mouse and human heart IHC of selected proteins underlying...
(A) Representative IHC heart images showing Comp protein expression (red) along with Tcf21 lineage–traced (EGFP+) fibroblasts from uninjured mice or the infarct region 7 and 28 days after MI. Nuclei are shown with DAPI (blue). Scale bars: 20 μm. (B) Representative IHC mouse heart images showing Chad protein expression (red) along with Tcf21 lineage–traced (EGFP+) fibroblasts from uninjured heart or the infarct region 7 and 28 days after MI. Nuclei are shown with DAPI (blue). The insets show higher magnification (×4) of double-positive cell for EGFP and Chad. Scale bars: 20 μm. (C) Representative IHC images showing protein expression of Chad (red), Comp (red), αSMA (red), Col3 (red), or vimentin (Vim, green) on the same or adjacent serial sections of ischemic LV human heart samples with scar and/or uninjured (control). Nuclei are shown with DAPI (blue). n = 3 (ischemic LVAD). n = 1 (healthy control). Scale bars: 20 μm.

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

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