The Role of the Extracellular Matrix in Inducing Cardiac Cell Regeneration and Differentiation

Abstract

The adult human heart has a limited ability to regenerate after injury, leading to the formation of fibrotic scars and a subsequent loss of function. In fish, mice, and humans, cardiac remodeling after myocardial injury involves the activation of epicardial and endocardial cells, pericytes, stem cells, and fibroblasts. The heart's extracellular matrix (ECM) plays a significant role in the regeneration and recovery process. The epicardium, endocardium, and pericytes reactivate the embryonic program in response to ECM stimulation, which leads to epithelial-mesenchymal transition, cell migration, and differentiation. This review analyzes the role of ECM in guiding the differentiation or dedifferentiation and proliferation of heart components by comparing significant findings in a zebrafish model with those of mammals.

Keywords: extracellular matrix; heart; zebrafish.

Figure 1

ECM’s role in inducing cardiac components. After ischemic damage, the first action in the site is alarmin emission (1) by endothelial cells of the capillary (V) and fibroblasts of the ECM (2). DAMP molecules activate apoptosis but also stimulate fibroblasts to produce FGFs. In parallel (3), fibroblasts and resident macrophages (M) begin producing IL-6, which stimulates the migration of leukocytes (LEU) to the damaged site. Simultaneously (4), the release of platelets, vitronectin, and metalloproteinases (MMP) takes place, which act to form a clot and manage the ECM structure. Fibroblasts are stimulated to produce new connective matrices like fibronectin, HA, laminins, GAG, and collagens. Fibronectin and GAGs are particularly involved in FGF release and other growth factors among the heart components. (5) The cellular heart components—epicardium (Ep), myocardium (Myo), endocardium (En), mural cells/pericytes (Mc), and cardiac stem/progenitor cells (CCs/CPCs)—are activated by several growth factors and by integrin/receptors/cadherins and, in turn, start to regulate key gene expressions that cause cells to de-differentiate and/or proliferate to repair the damage site (panels). The key gene expression is comparable between mammals (A) and fish (B); however, the speed of cellular replacement in mammals is low compared with that in fish, and a large amount of ECM is secreted by fibroblasts in the process of recovering the damaged tissue, provoking a fibrotic scar.