Cross talk between cardiac myocytes and fibroblasts: from multiscale investigative approaches to mechanisms and functional consequences

Abstract

The heart is comprised of a syncytium of cardiac myocytes (CM) and surrounding nonmyocytes, the majority of which are cardiac fibroblasts (CF). CM and CF are highly interspersed in the myocardium with one CM being surrounded by one or more CF. Bidirectional cross talk between CM and CF plays important roles in determining cardiac mechanical and electrical function in both normal and diseased hearts. Genetically engineered animal models and in vitro studies have provided evidence that CM and CF can regulate each other's function. Their cross talk contributes to structural and electrical remodeling in both atria and ventricles and appears to be involved in the pathogenesis of various heart diseases that lead to heart failure and arrhythmia disorders. Mechanisms of CM-CF cross talk, which are not yet fully understood, include release of paracrine factors, direct cell-cell interactions via gap junctions and potentially adherens junctions and nanotubes, and cell interactions with the extracellular matrix. In this article, we provide an overview of the existing multiscale experimental and computational approaches for the investigation of cross talk between CM and CF and review recent progress in our understanding of the functional consequences and underlying mechanisms. Targeting cross talk between CM and CF could potentially be used therapeutically for the modulation of the cardiac remodeling response in the diseased heart and may lead to new strategies for the treatment of heart failure or rhythm disturbances.

Fig. 1.

Schematic diagram illustrating potential mechanism of cross talk between cardiac myocytes (CM) and cardiac fibroblasts (CF), along with respective CM and CF functions and the remodeling changes that ensue in the diseased heart. See text for details on the evidence in support of each mechanism in cocultures in vitro and the intact myocardium in vivo. MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases.

Fig. 2.

Approaches to investigate cross talk between CM and CF. Experimental models (top) and computational models (bottom). *The reconfigurable two-dimensional (2-D) coculture approach has not yet been used for investigating cross talk between CM and CF. 3-D, three dimensional. See text for details.