Engineering cardiac microphysiological systems to model pathological extracellular matrix remodeling

Abstract

Many cardiovascular diseases are associated with pathological remodeling of the extracellular matrix (ECM) in the myocardium. ECM remodeling is a complex, multifactorial process that often contributes to declines in myocardial function and progression toward heart failure. However, the direct effects of the many forms of ECM remodeling on myocardial cell and tissue function remain elusive, in part because conventional model systems used to investigate these relationships lack robust experimental control over the ECM. To address these shortcomings, microphysiological systems are now being developed and implemented to establish direct relationships between distinct features in the ECM and myocardial function with unprecedented control and resolution in vitro. In this review, we will first highlight the most prominent characteristics of ECM remodeling in cardiovascular disease and describe how these features can be mimicked with synthetic and natural biomaterials that offer independent control over multiple ECM-related parameters, such as rigidity and composition. We will then detail innovative microfabrication techniques that enable precise regulation of cellular architecture in two and three dimensions. We will also describe new approaches for quantifying multiple aspects of myocardial function in vitro, such as contractility, action potential propagation, and metabolism. Together, these collective technologies implemented as cardiac microphysiological systems will continue to uncover important relationships between pathological ECM remodeling and myocardial cell and tissue function, leading to new fundamental insights into cardiovascular disease, improved human disease models, and novel therapeutic approaches.

Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review

“…The extracellular cardiac matrix (ECM), which is a complex architectural network, maintains a balance between the degradation and deposition of matrix proteins by preserving the correct cardiac geometry whilst also allowing the myocardium to maintain its structural integrity [ 137 ]. The ECM aids in the proper functioning of heart cells, forming a specific scaffold which allows for the anchoring of these proteins [ 138 ]. A range of physiological and pathological processes, such as cell proliferation and differentiation, and tissue morphogenesis, are influenced by the ECM turnover [ 139 ].…”

Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review

“…The extracellular cardiac matrix (ECM), a complex architectural network, maintains equilibrium between the deposition and degradation of matrix proteins by preserving the correct cardiac geometry and structural integrity of the myocardium [150]. The ECM aids heart cells to function properly by forming a specific scaffold which allows for the anchoring of these proteins [151].…”

“…Matrix metalloproteinases (MMPs) are enzymes capable of degrading ECM structural proteins and their endogenous tissue inhibitors of metalloproteinases (TIMPs). They are the main mediators of ECM remodelling [150]. These processes are tightly regulated under normal conditions.…”

Maladaptive Contractility of 3D Human Cardiac Microtissues to Mechanical Nonuniformity

“…[ 10–13 ] In native myocardium, as well as these cardiac tissue models, the mechanical environment plays an important role in either maintenance of physiological functions or inducement of pathological dysfunctions. [ 14–18 ] For example, optimal substrate stiffness based on polyacrylamide has been demonstrated to promote maximal contractile force from micropatterned single hiPSC‐derived cardiomyocytes (hiPSC‐CMs). [ 19 ] Alternatively, the maturation level of hiPSC‐CMs can be improved by gradually increasing stimulation intensity starting at the early stages, rather than constant stimulations.…”