"Specialized fibroblast differentiated states underlie scar formation i" by Xing Fu, Hadi Khalil et al.

Faculty Publications

Title

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

Authors

Xing Fu, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Hadi Khalil, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Onur Kanisicak, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Justin G. Boyer, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Ronald J. Vagnozzi, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Bryan D. Maliken, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Michelle A. Sargent, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.

Document Type

Article

Publication Date

5-1-2018

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.

Publication Source (Journal or Book title)

The Journal of clinical investigation

First Page

2127

Last Page

2143

Recommended Citation

Fu, X., Khalil, H., Kanisicak, O., Boyer, J. G., Vagnozzi, R. J., Maliken, B. D., & Sargent, M. A. (2018). Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. The Journal of clinical investigation, 128 (5), 2127-2143. https://doi.org/10.1172/JCI98215

Link to Full Text

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