Abstract
Cardiac fibrosis is one of the most devastating effects of cardiac disease. Current in vitro models of cardiac fibrosis do not sufficiently mimic the complex in vivo environment of the cardiomyocyte. We determined the local composition and mechanical properties of the myocardium in established mouse models of genetic and acquired fibrosis and tested the effect of myocardial composition on cardiomyocyte contractility in vitro by systematically manipulating the number of fibroblasts and collagen concentration in a platform of engineered cardiac microtissues. The in vitro results showed that while increasing collagen content had little effect on microtissue contraction, increasing fibroblast density caused a significant reduction in contraction force. In addition, the beating frequency dropped significantly in tissues consisting of 50% cardiac fibroblasts or higher. Despite apparent dissimilarities between native and in vitro fibrosis, the latter allows for the independent analysis of local determinants of fibrosis, which is not possible in vivo.
Highlights
The heart consists of cardiomyocytes, fibroblasts, and other cardiac cells that are supported by a complex meshwork of fibers, the cardiac extracellular matrix (ECM)
Immunohistological analysis for collagen I and III and fibronectin was performed on the fibrotic areas of both mdx and transverse aortic constriction (TAC) left ventricles
It has frequently been reported that fibroblast proliferation inhibits the contractility of cardiomyocytes, here, we demonstrated a threshold value of 50% fibroblasts above which synchronized beating was severely hampered
Summary
The heart consists of cardiomyocytes, fibroblasts, and other cardiac cells that are supported by a complex meshwork of fibers, the cardiac extracellular matrix (ECM). In case of cardiac disease, the heart is subject to changes in composition and structure, often leading to cardiac fibrosis. Engineered cardiac tissues are excellent models to mimic and study normal and diseased cardiac development and physiology and open new avenues for therapy assessment. The tissues can be cultured under highly controlled conditions and give insights into the responses of cells and ECM on isolated biochemical and biophysical stimuli, which would be impossible to study in vivo. To apply such tissue models as therapy screening platforms, it is important that the models
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