Mar 27, 2020

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

Matrix Biology : Journal of the International Society for Matrix Biology
Angela C. ZeiglerJeffrey J Saucerman

Abstract

The fibroblast is a key mediator of wound healing in the heart and other organs, yet how it integrates multiple time-dependent paracrine signals to control extracellular matrix synthesis has been difficult to study in vivo. Here, we extended a computational model to simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction (MI) in response to time-dependent data for nine paracrine stimuli. This computational model was validated against dynamic collagen expression and collagen area fraction data from post-infarction rat hearts. The model predicted that while many features of the fibroblast phenotype at inflammatory or maturation phases of healing could be recapitulated by single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking the reparative phase required paired stimuli (e.g. TGFβ and endothelin-1). Virtual overexpression screens simulated with either static cytokine pairs or post-MI paracrine dynamic predicted phase-specific regulators of collagen expression. Several regulators increased (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the reparative phase. NADPH oxidase (NOX) overexpression sustained collagen expression from rep...Continue Reading

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Mentioned in this Paper

Bone morphogenetic protein 2
Protein Expression
Signal Pathways
In Vivo
Heart Rupture, Post-Infarction
Collagen
Rat Heart
Post MI
NOX1
Cytokine

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