Basic Biology of Extracellular Matrix in the Cardiovascular System, Part 1/4: JACC Focus Seminar

Abstract

The extracellular matrix (ECM) is the noncellular component of tissues in the cardiovascular system and other organs throughout the body. It is formed of filamentous proteins, proteoglycans, and glycosaminoglycans, which extensively interact and whose structure and dynamics are modified by cross-linking, bridging proteins, and cleavage by matrix degrading enzymes. The ECM serves important structural and regulatory roles in establishing tissue architecture and cellular function. The ECM of the developing heart has unique properties created by its emerging contractile nature; similarly, ECM lining blood vessels is highly elastic in order to sustain the basal and pulsatile forces imposed on their walls throughout life. In this part 1 of a 4-part JACC Focus Seminar, we focus on the role, function, and basic biology of the ECM in both heart development and in the adult.

Keywords: cardiovascular; collagen; development; homeostasis; matrix.

Figure 1.. Overview of the main cardiac developmental processes regulated by Extracellular Matrix (ECM) components or ECM degradation.

(A) Early cardiac progenitor formation; (B) cardiac looping; (C) cardiac chamber development and trabeculation; (D) vessel development; (E) cardiac valve development. OFT, outflow tract; RV, right ventricle; LV, left ventricle; AVC, atrioventricular canal; A, atrium; DA, dorsal aorta; TM, trabecular myocardium; ECM, extracellular matrix; CM, compact myocardium; EC, endocardium; MYO, myocardium.

Figure 2.. Hyaluronan and Hyaluronan Binding Proteins.

Hyaluronan (HA) matrix diversification via HA binding proteins highlights its multifunctionality. HA’s function is diversified by HA binding proteins that specifically bind via a link module domain. For example, interaction with versican, a large chondroitin sulfate proteoglycan can lead to large hydrated aggregates that allow cell migration and proliferation. Versican can also bring together other ECM components (e.g. fibronectin, tenascin-R, and microfibrils) via its C terminal domain (106). During inflammation HA can be covalently modified by the addition of heavy chains 1, −2 (HC1, −2) from inter-α-inhibitor, a process mediated by TSG6, resulting in an ECM that is highly adhesive for leukocytes. HA can also be cross-linked by TSG6 resulting in a more condensed ECM, of which the full implications are unknown (76).

Figure 3.. Cellular sources of ECM production in cardiac tissue revealed by single-cell RNA sequencing.

ScRNAseq of the total interstitial, non-cardiomyocyte, cell population of control hearts. (A) Heatmap of ECM gene ontology (GO) term expression across all populations, confirming the highest expression of ECM is generated by fibroblasts. (B) t-distributed stochastic neighbor embedding (tSNE) plot of cell population clusters showing that the major cell types, i.e. fibroblasts and endothelial cells, can be subdivided into 5 distinct fibroblast sub-populations (F-SL, F-SH, F-Act, F-WntX and MYO) and 3 distinct endothelial cell populations (EC1, −2, −3). (C) tSNE plots showing the expression patterns of collagen type I, collagen type IV, TGF-β1 and laminin subunit beta-3. Figure generated using data made available by Farbehi et al. (119). F-SL, fibroblast-Sca1-low; F-SH, fibroblast-Sca1-high; F-Act, fibroblast-activated; F-WntX, fibroblast-Wnt expressing; MYO, myofibroblast; EC1–3, endothelial cell 1–3; M1Mo, M1 monocyte; M1MФ, M1 macrophage; M2MФ, M2 macrophage; MAC-IFNIC, macrophage-IFN inducible cell; MAC-TR, macrophage-tissue resident; MAC6–8, macrophage 6–8; DC, dendritic cell; BC, B-cell; TC1-Cd8, T-Cell 1-Cd8+; TC2-Cd4, T-cell 2-Cd4+; NKC, natural killer cell; Cyc, cycling cell.

Figure 4.. Gene expression profile of major ECM- and ECM-associated components in the non-myocytic cell populations of healthy adult myocardium.

(A) Graphical representation of the cellular composition and ECM organization in the myocardium. (B) Heatmaps of ECM gene expression from scRNAseq analysis of control hearts. Figure generated using data made available by Farbehi et al. (119). Abbreviations as per Figure 3.

Central Illustration.. Organization of Cardiac and Vascular Extracellular Matrix (ECM).

Cardiovascular tissues face different hemodynamic and mechanical requirements which have resulted in a unique building plan and highly specialized ECM and cellular compositions. Prominent sub-structures and ECM components are indicated.