Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: Mechanisms and model systems

Abstract

Development of cardiac fibrosis and arrhythmias is controlled by the activity of and communication between cardiomyocytes and fibroblasts in the heart. Myocyte-fibroblast interactions occur via both direct and indirect means including paracrine mediators, extracellular matrix interactions, electrical modulators, mechanical junctions, and membrane nanotubes. In the diseased heart, cardiomyocyte and fibroblast ratios and activity, and thus myocyte-fibroblast interactions, change and are thought to contribute to the course of disease including development of fibrosis and arrhythmogenic activity. Fibroblasts have a developing role in modulating cardiomyocyte electrical and hypertrophic activity, however gaps in knowledge regarding these interactions still exist. Research in this field has necessitated the development of unique approaches to isolate and control myocyte-fibroblast interactions. Numerous methods for 2D and 3D co-culture systems have been developed, while a growing part of this field is in the use of better tools for in vivo systems including cardiomyocyte and fibroblast specific Cre mouse lines for cell type specific genetic ablation. This review will focus on (i) mechanisms of myocyte-fibroblast communication and their effects on disease features such as cardiac fibrosis and arrhythmias as well as (ii) methods being used and currently developed in this field.

Keywords: Arrhythmia; Cardiomyocyte; Cell-cell interactions; Fibroblast; Fibrosis.

Figure 1

Cardiomyocyte-fibroblast interactions. Various interactions between cardiomyocytes and fibroblasts in the heart are diagrammed above with emphasis on the following categories: (A) biochemical (paracrine signals), (B) electrical (connexins and membrane nanotubes), and (C) biomechanical (ECM and mechanical junctions). Specific signal-carrying proteins or structures are shown below their corresponding category. The responses of cardiomyocytes and fibroblasts to these signals are shown to the right of each diagram. Red arrows next to each type of interaction notate whether an increase (up arrow) or decrease (down arrow) lead to the disease features presented.