Effect of Cyclic Strain on Cardiomyocytes and Fibroblasts and Its Relation to Heart Disease*

The heart is a dynamic mechanical environment, and both cardiomyocytes and fibroblasts play an important role in myocardium function. Both the mechanics and cell composition of the myocardium changes in pathology. The interplay between the cell phenotype and mechanical stimulation needs to be considered to understand the biophysical cell interactions in healthy and diseased myocardium. The design is challenged by the different response of fibroblasts and cardiomyocytes to the cyclic stretching. Indeed, in isolation the fibroblasts orient perpendicular to cyclic strain, while the cardiomyocytes will align parallel. This is in contradiction to the cellular architecture in a healthy heart. In this work, we hypothesized that the dominant cell type dictates the overall tissue organization in the heart, which would explain the tendency toward disorganization in fibrotic regions of the heart. To test this, the cardiomyocytes and fibroblasts were co-cultured at different ratios in a cyclic stretcher that mimicked the dominant mechanical strain of the heart. Image processing software was designed to analyze the cytoskeleton architecture of the two cell types separately. The overall and local organization was evaluated using the orientational order parameter and compared among all conditions. The cardiomyocytes and fibroblasts were found to orient perpendicular to each other if there was no cell-to-cell contact. Conversely, they were found to influence each other’s orientation in a confluent co-culture. The cells likely influence each other through both mechanical coupling over adherens junctions and physical space limitations. These results elucidate some of the reorganization observed pathologically when fibroblasts dominate a portion of the myocardium.