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.

Effects of Simulated Microgravity on Wild Type and Marfan hiPSCs-Derived Embryoid Bodies

“…This finding was also confirmed by the histomorphometrical analysis on toluidine blue- stained semi-thin sections that revealed a bigger size of WT and MFS EBs under SMG, whereas a comparable ratio between matrix and cell area under 1g and SMG conditions at day 7. The transcription analysis for ECM genes revealed that, elastin, one of the major non-collagenous component of the interstitial ECM, 17,35 did not significantly change in WT and MFS under SMG condition in 7-day old EBs. There was just an early up-regulation of COL8A1 and COL12A1 in WT under SMG condition, but these two molecules only represent minor ECM components that form networks between the different matrix elements by associating to collagen I-containing fibrils.…”

“…There was just an early up-regulation of COL8A1 and COL12A1 in WT under SMG condition, but these two molecules only represent minor ECM components that form networks between the different matrix elements by associating to collagen I-containing fibrils. 17,35 So, there is no evidence of a significant alteration in ECM composition in MFS compared with WT EBs. The downregulation of some genes involved in ECM organization and cell-cell adhesion in WT and MFS EBs, along day 14 and 22 under SMG condition, could be probably due to a compensatory phenomenon.…”

“…13 Results are contradictory, due the different study designs in terms of alternative microgravity simulation (clinorotation vs. Random Position machine) or cell culturing technologies. 15,20,34 Anyway, up to date there are few studies on the cellular responses of embryonic stem cells to SMG condition 35 and none on hiPSC-derived EBs.…”

Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases

“…However, if stressful events are sustained, remodeling may end up causing a progressive and irreversible dysfunction, resulting in an excessive extracellular matrix (ECM) deposition and induction of pro-fibrotic events [ 20 , 21 ]. The cardiac ECM is mainly composed of fibrillar forming collagen (types I and III), but it can also be rich in other non-fibrillar components such as type IV collagen, glycosaminoglycans, glycoproteins, proteoglycans, fibrin, fibronectin, elastin and laminin [ 22 , 23 , 24 ]. ECM is also a reservoir of growth factors, cytokines, chemokines, proteases and their inhibitors and microRNAs [ 22 ], which play important roles in fibroblasts proliferation, migration and transdifferentiation.…”

A Brief History in Cardiac Regeneration, and How the Extra Cellular Matrix May Turn the Tide

“…The regenerative potential of zebrafish and of neonatal mammals is truly astonishing, and to this day still baffles the scientific community. In spite of this, recent advances in stem cell biology, molecular biology, and matrix biology have started to unravel this mystery and suggested a key role in cardiac regeneration is played by the constitution of the ECM ( 36 , 37 ). One of the earliest studies to focus on the regenerative potential of the ECM, utilized decellularized zebrafish cardiac ECM and injected this ECM solution into a murine MI model ( 38 ).…”