Bearing My Heart: The Role of Extracellular Matrix on Cardiac Development, Homeostasis, and Injury Response

Abstract

The extracellular matrix (ECM) is an essential component of the heart that imparts fundamental cellular processes during organ development and homeostasis. Most cardiovascular diseases involve severe remodeling of the ECM, culminating in the formation of fibrotic tissue that is deleterious to organ function. Treatment schemes effective at managing fibrosis and promoting physiological ECM repair are not yet in reach. Of note, the composition of the cardiac ECM changes significantly in a short period after birth, concurrent with the loss of the regenerative capacity of the heart. This highlights the importance of understanding ECM composition and function headed for the development of more efficient therapies. In this review, we explore the impact of ECM alterations, throughout heart ontogeny and disease, on cardiac cells and debate available approaches to deeper insights on cell-ECM interactions, toward the design of new regenerative therapies.

Keywords: cardiac ontogeny; cardiovascular diseases; decellularization; extracellular matrix; fibrosis; heart; regeneration.

FIGURE 1

Overview of mouse heart development, maturation, and aging. FN from primitive ECM paves the way for the migration of cardiac progenitor cells (cardiac crescent) to the embryo midline. Upon fusion, cardiac progenitor cells form the heart tube. The latter is constituted by two cell layers—the myocardium (outer layer) and the endocardium (inner layer)—separated by an amorphous matrix known as the cardiac jelly. The heart starts looping (looping heart) toward the formation of a four-chambered organ. In parallel, endocardial cells invade the cardiac cushion, that is, an extensive accumulation of cardiac jelly at primitive valve structures, and undergo EndoMT, forming valve tissue cells. The heart evolves, and the size of the myocardium increases while cardiomyocytes proliferate and mature at the compact and trabecular layers, respectively. Compaction and trabeculation are regulated by the transient expression of nephronectin and by the enzymatic degradation of the versican promoted by ADAMTs (fetal heart). After birth, the ECM undergoes extensive remodeling characterized by a decrease in hyaluronic acid, FN, and proteoglycans. At the same time, cardiomyocytes cease proliferation and finalize maturation, acquiring robust sarcomeres and a rod-shaped morphology (postnatal–adult heart). Aging contributes to functional impairment by the loss of cardiomyocytes and formation of fibrotic tissue (aged heart). Blue box, specific morphological events regulated by the ECM; black box, variations on ECM composition throughout ontogeny.

FIGURE 2

ECM dynamics during tissue repair after MI. Progressive changes in the composition of the ECM occur during the three overlapping phases of the injury response: inflammatory, proliferative, and maturation phases. At the extracellular space, the main remodeling events encompass the degradation of the interstitial matrix (dark yellow lines), production and resolution of the provisional ECM (green lines), and lastly, scar formation (blue lines). Firstly, the release of inflammatory mediators by dead cells leads to the recruitment of leukocytes and neutrophil activation (pink cells) and increases vascular permeability and MMP expression and activity. The latter degrades the interstitial matrix (yellow), generating bioactive fragments (matrikines) that contribute to the inflammatory cascade. From the extravasated plasma proteins, a fibrin- and FN-based matrix network is formed (provisional ECM, green). This transient ECM is rich in growth factors and inflammatory cytokines and serves as a highly permeable conduit for cells. Fibroblasts (gray cells) adhere to this matrix, initiate the repair of the damaged area through proliferation and differentiation in myofibroblasts (myoFBs), and secrete different ECM molecules, such as proteoglycans (PGs), hyaluronan, and versican, that stabilize this provisional ECM. During the proliferative phase, myoFBs deposit large amounts of structural ECM proteins, mostly collagens, to preserve the integrity of the myocardial wall, and the provisional matrix is degraded. As the maturation phase initiates, the collagen content increases, and enzymes such as LOX are upregulated, inducing collagen cross-linking and the formation of a rigid scar.

FIGURE 3

Cardiac decellularization. Decellularization aims to remove the cellular compartment of a tissue, while preserving the composition and architectural arrangement of the ECM. This can be achieved by combined application of physical, enzymatic, and chemical treatments.

FIGURE 4

ECM composition during regenerative (fetal/neonate) and reparative (adult) stages. The composition of the ECM changes around birth, resulting in a stiffer and less regenerative environment. In the fetal–neonatal heart, agrin and periostin stimulate cardiomyocyte proliferation and neovascularization, thus promoting regeneration of the tissue. During adult heart repair, increased expression of fetal-associated ECM is observed, namely, through the expression of FN and hyaluronan. However, this reactivation of the fetal program is incomplete, and adult cardiomyocytes are unable to proliferate, resulting in the formation of a collagen-rich scar.