Cardiac Extracellular Matrix Modification as a Therapeutic Approach

Abstract

The cardiac extracellular matrix (cECM) is comprised of proteins and polysaccharides secreted by cardiac cell types, which provide structural and biochemical support to cardiovascular tissue. The roles of cECM proteins and the associated family of cell surface receptor, integrins, have been explored in vivo via the generation of knockout experimental animal models. However, the complexity of tissues makes it difficult to isolate the effects of individual cECM proteins on a particular cell process or disease state. The desire to further dissect the role of cECM has led to the development of a variety of in vitro model systems, which are now being used not only for basic studies but also for testing drug efficacy and toxicity and for generating therapeutic scaffolds. These systems began with 2D coatings of cECM derived from tissue and have developed to include recombinant ECM proteins, ECM fragments, and ECM mimics. Most recently 3D model systems have emerged, made possible by several developing technologies including, and most notably, 3D bioprinting. This chapter will attempt to track the evolution of our understanding of the relationship between cECM and cell behavior from in vivo model to in vitro control systems. We end the chapter with a summary of how basic studies such as these have informed the use of cECM as a direct therapy.

Extracellular Matrix in Regulation of Contractile System in Cardiomyocytes

“…The mechanisms underlying are likely to be mediated by transmembrane integrin receptors (see Figure 1). However, the in vivo investigation of integrin engagement and following signaling pathways is limited by the complex organization of heart tissue, which makes it difficult to isolate the effects of individual ECM proteins on particular cell processes [44]. In vitro investigations on the cells induced for cardiogenic differentiation are still ineffective because of the heterogeneity of cell population varying in lineages and stages of differentiation.…”

“…There are some excellent reviews that describe the composition and distribution of ECM in heart tissue [37] and characterize its alterations during heart development [13,38] and aging [39]. The role of ECM turnover in heart physiology as well as heart pathology has been overviewed [40,41,42,43] and the effect of natural as well as synthetic ECM for the proliferation, attachment, and differentiation of different heart cells has been evaluated [44].…”

“…Another important component of myocardial ECM is fibronectin, which has been implicated in cell adhesion, being crucial for cell binding to other ECM components. Fibronectin was shown to be essential for heart development and repair [44].…”

Progress in cardiovascular bioprinting

“…Though, a variety of scaffold polymers are studied extensively, most of the 3D cardiovascular bioprinting efforts have used natural materials such as collagen, fibrin, elastin, laminin, and fibronectin. These natural materials offer structural strength and compliance, and favor new blood vessel formation 56‐60 …”

Engineering of thick human functional myocardium via static stretching and electrical stimulation

“…Both active and passive mechanical stimulation ( Tulloch et al., 2011 ; Hirt et al., 2012 ; Mihic et al., 2014 ; Rogers et al., 2016 ; Ruan et al., 2016 ; Leonard et al., 2018 ), simulating the various loading phenomena observed in the heart, as well as highly controlled regimens of chronic, electrical stimulation ( Tandon et al., 2009 , 2011 ; Nunes et al., 2013 ; Hirt et al., 2014 ; Eng et al., 2016 ) have been employed, each showing promising improvements to structural or functional aspects of hiPSC-CM development. In addition, 3D engineering of the ECM environment has also aided in maturation by providing a structured environment for the cells to both efficiently connect and communicate while also providing a means for them to organize more akin to what is observed in adult heart tissue ( Jung et al., 2016 ; Mills et al., 2017 ; Hall and Ogle, 2018 ).…”