Abstract
In the cardiac microenvironment, cardiomyocytes (CMs) are embedded in an aligned and structured extracellular matrix (ECM) to maintain the coordinated contractile function of the heart. The cardiac fibroblast (cFB) is the main cell type responsible for producing and remodeling this matrix. In cardiac diseases, however, adverse remodeling and CM death may lead to deterioration of the aligned myocardial structure. Here, we present an in vitro cardiac model system with uniaxial and biaxial constraints to induce (an)isotropy in 3D microtissues, thereby mimicking 'healthy' aligned and 'diseased' disorganized cardiac matrices. A mixture of neonatal mouse CMs and cFBs was resuspended in a collagen-matrigel hydrogel and seeded to form microtissues to recapitulate the in vivo cellular composition. Matrix disarray led to a stellate cell shape and a disorganized sarcomere organization, while CMs in aligned matrices were more elongated and had aligned sarcomeres. Although matrix disarray has no detrimental effect on the force generated by the CMs, it did have a negative effect on the homogeneity of contraction force distribution. Furthermore, proliferation of the cFBs affected microtissue contraction as indicated by the negative correlation between the percentage of cFBs in the microtissues and their beating frequency. These results suggest that in regeneration of the diseased heart, reorganization of the disorganized matrix will contribute to recover the coordinated contraction but restoring the ratio in cellular composition (CMs and cFBs) is also a prerequisite to completely regain tissue function.
Highlights
Introduction a Department of BiomedicalEngineering, Eindhoven University of Technology, Eindhoven, The Netherlands
The myocardial microenvironment is composed of cardiomyocytes (CMs) and non-myocytes embedded in an aligned and structured extracellular matrix (ECM), which is mainly produced by the cardiac fibroblasts.[1]
Confocal microscopy on microtissues stained with CNA-35 OG and CTO at day two, four, and seven showed that cells were embedded in a collagen matrix and distributed homogenously throughout the microtissues in both designs (Fig. 1B)
Summary
E-mail: a.c.c.v.spreeuwel@tue.nl b Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA c Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA d The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA e Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands † Electronic supplementary information (ESI) available. The myocardial microenvironment is composed of cardiomyocytes (CMs) and non-myocytes embedded in an aligned and structured extracellular matrix (ECM), which is mainly produced by the cardiac fibroblasts (cFBs).[1] Cells and ECM proteins are connected via cell–cell and cell–matrix interactions to maintain this structural organization and enable coordinated contraction of the heart During cardiac disease, such as ischemia and myocardial infarction, the myocardial microenvironment changes in response to pathological cues. The most common effects of heart disease are loss of CMs, followed by tissue repair and remodeling,
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