Mimicking Cardiac Fibrosis in a Dish: Fibroblast Density Rather than Collagen Density Weakens Cardiomyocyte Function

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. Electronic supplementary materialThe online version of this article (doi:10.1007/s12265-017-9737-1) contains supplementary material, which is available to authorized users.

Multiscale Coupling of an Agent-Based Model of Tissue Fibrosis and a Logic-Based Model of Intracellular Signaling

“…Application of this coupled model in the context of post-MI wound healing will allow for further investigation and validation of cytokine concentrations, collagen content and heterogeneity, and cell behaviors with both fine spatial and temporal resolution. Experimental studies suggest that collagen density alone may have effects on fibroblast behavior, including adhesion, migration, and gene expression (Loftis et al, 2003), and that furthermore, collagen density and fibroblast density play an important role in the mechanical properties of the myocardium (Fomovsky et al, 2012;van Spreeuwel et al, 2017). This multiscale model framework allows for further investigation and understanding of emergent phenomena that result from the dynamic interplay between molecular signaling, cell behavior, ECM composition, and tissue mechanics.…”

Modelling cardiac fibrosis using three-dimensional cardiac microtissues derived from human embryonic stem cells

“…An improvement of in vitro cell or tissue models may open up new possibilities for disease modelling, drug discovery, and regenerative medicine by providing fast and controllable platforms with high availability and relatively low cost compared to animal models. As yet, few in vitro models of cardiac fibrosis have been developed [8–12]. Most are composed of cardiac cells derived from neonatal mouse and rat hearts and thus have less relevance to human pathophysiology.…”

Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism

“…Previously, exogenous TGF-β1 has been shown to induce fibrosis in rat [17,18] or human [19] cardiac microtissue models. Furthermore, fibrotic phenotypes in cardiac microtissues or in biowire were also produced by collagen/fibroblast enrichment [20,21] or by constitutive activation of profibrotic pathways [22].…”