Densification of Type I Collagen Matrices as a Model for Cardiac Fibrosis

Abstract

Cardiac fibrosis is a disease state characterized by excessive collagenous matrix accumulation within the myocardium that can lead to ventricular dilation and systolic failure. Current treatment options are severely lacking due in part to the poor understanding of the complexity of molecular pathways involved in cardiac fibrosis. To close this gap, in vitro model systems that recapitulate the defining features of the fibrotic cellular environment are in need. Type I collagen, a major cardiac ECM protein and the defining component of fibrotic depositions, is an attractive choice for a fibrosis model, but demonstrates poor mechanical strength due to solubility limits. However, plastic compression of collagen matrices has been shown to significantly increase its mechanical properties. Here, we utilized confined compression of oligomeric, type I collagen matrices to resemble defining hallmarks seen in fibrotic tissue such as increased collagen content, fibril thickness and bulk compressive modulus. Cardiomyocytes seeded on compressed matrices show a strong beating abrogation as observed in cardiac fibrosis. Gene expression analysis of selected fibrosis markers indicated fibrotic activation and cardiomyocyte maturation with regard to the existing literature. With these results, we present a promising first step towards a facile heart-on-chip model to study cardiac fibrosis.

Cardioprotective Effects of Dietary Flaxseed Post-Infarction Are Associated with Changes in MicroRNA Expression

“…Increased accumulation of fibrillar collagen in the cardiac matrix is a hallmark of myocardial fibrosis [ 37 ]. Type I collagen is the most abundant as it accounts for 85% of the collagen content within the myocardium [ 38 ]. Previous work from our lab has shown increased histochemical staining after an MI induced by coronary artery ligation as evidence of increased myocardial fibrosis [ 22 ].…”

miR‑155 modulates high glucose‑induced cardiac fibrosis via the Nrf2/HO‑1 signaling pathway

“…Progressive cardiac fibrosis is associated with myocardial infarction, hypertrophy, hypertension, heart failure and other cardiovascular diseases (1). However, current therapies for cardiac fibrosis are severely limited and inefficient (32).…”

“…cardiac fibrosis is a worldwide health issue associated with nearly all forms of heart disease, such as ventricular dilation and heart failure (1), which accounts for nearly 31% of all deaths each year (2). Fibrosis pathogenesis mainly involves inappropriate fibroblast accumulation and excess collagen deposition in the myocardium (3), which is accompanied by excessive oxidative stress and apoptosis or necrosis of cardiomyocytes (4).…”

Dynamic and static biomechanical traits of cardiac fibrosis

“…This work showed how cell shape affects the cellular response to 3D mechanical and biochemical cues, and has implications for the development of cell shape modulation-specific approaches to treat fibrosis. Worke et al (2017) have also explored the potential of compressed collagen matrix as a structure mechano-chemical and physiochemical related cardiac fibrosis model system by combining collagen with embryonic cardiomyocytes. In brief, these models provide us with strong support to study static biomechanics of cardiac fibrosis in vitro and test anti-fibrotic drugs in promoting real-time assessment of cardiomyocyte function.…”