The role of the extracellular matrix in cardiac regeneration

Abstract

The extracellular matrix (ECM) is a complex and dynamic three-dimensional network that functions as an architectural scaffold to maintain cardiac homeostasis. Important biochemical and mechanical signals associated with cell‒cell communication are provided via the reciprocal interaction between cells and the ECM. By converting mechanical cues into biochemical signals, the ECM regulates many cell processes, including migration, adhesion, growth, differentiation, proliferation, and apoptosis. Moreover, the ECM facilitates the replacement of dead cells and preserves the structural integrity of the heart, making it essential in conditions such as myocardial infarction and other pathological states. When excessive ECM deposition or abnormal production of ECM components occurs, the heart undergoes fibrosis, leading to cardiac dysfunction and heart failure. However, emerging evidence suggests that the ECM may contribute to heart regeneration following cardiac injury. The present review offers a complete overview of the existing information and novel discoveries regarding the involvement of the ECM in heart regeneration from both mechanical and biochemical perspectives. Understanding the ECM and its involvement in mechanotransduction holds significant potential for advancing therapeutic approaches in heart repair and regeneration.

Keywords: Extracellular matrix; Fibroblasts; Heart failure; Heart regeneration; Mechanics.

Fig. 1

Schematic depiction of the matrix composition and physiological properties. The ECM is a noncellular three-dimensional polymer network that exists in all tissues and organs. It serves as a physical scaffold for cellular embedding that initiates vital biomechanical and biochemical signals necessary for tissue differentiation, development, and homeostasis. Collagen accounts for 30 % of the total mammalian protein content and is found in fibril and nonfibril forms. Collagen is synthesized and secreted by fibroblasts, provides structural strength to all forms of the ECM and limits the distensibility of tissues. Glycoproteins mainly include elastin, laminin, and FN, which have diverse functions. Elastin is responsible for conferring elastic properties to tissues that experience repetitive stretching. FN and laminin bind to cell surface receptors (such as integrins) and influence cell adhesion, differentiation, and migration. PGs are composed of a core protein with coupled GAGs and participate in space filling and lubrication. PGs can bind many cytokines, growth factors, and chemokines in the ECM. Owing to their capacity to engage with additional ECM molecules and cell surface receptors and activate a variety of signal transduction pathways, PGs perform essential functions in ECM remodelling and physiological and pathological processes. DDRs: discoidin domain receptors; GF: growth factor; HA: hyaluronan.

Fig. 2

The ECM during cardiac regeneration. Mechanical stress activates the matrix-preserving fibroblast phenotype and induces the production of MMPs and TIMPs, which cause ECM remodelling. The alteration of ECM components modulates the proliferation and differentiation of CMs, among which FN, agrin and periostin are three important bioactive factors that regulate cardiac regeneration. FN is mainly secreted as a soluble protein by different cell types, such as CFs and endothelial cells (ECs), and is deposited after heart injury. It can regulate CM proliferation, which is mediated by β1 integrin. Agrin is a large matrix proteoglycan that is mainly secreted by ECs and acts as a ligand for a variety of receptors. In vivo and in vitro, the addition of agrin promotes the growth and differentiation of CMs through Yap-DGC-mediated signalling. Periostin is absent in healthy myocardium, and pathological injury stimulates the production and secretion of periostin through activated fibroblasts. In an adult mouse model of MI, exogenous expression of periostin has been shown to augment myocardial development following injury and facilitate the process of cardiac repair, thereby improving ventricular remodelling and function.