Heart failure is a progressive deterioration of cardiac pump function over time and is often a manifestation of ischemic injury caused by myocardial infarction (MI). and promote functional recovery. Acellular ECM bioscaffolds have been shown to provide passive structural support to the damaged myocardium and also to act as a dynamic bioactive reservoir capable of promoting RG3039 endogenous mechanisms of tissue repair, such as vasculogenesis. The composition and structure of xenogenic acellular ECM bioscaffolds are determined by the physiological requirements of the tissue from which they are derived. The capacity of different tissue-derived acellular RG3039 bioscaffolds to attenuate cardiac remodeling and restore ECM homeostasis after injury may depend on such properties. Accordingly, the search and discovery of an optimal ECM bioscaffold for use in cardiac repair is warranted and may be facilitated by comparing bioscaffolds. This review RG3039 will provide a summary of the acellular ECM bioscaffolds currently available for use in cardiac surgery with a focus on how they attenuate cardiac remodeling by providing the necessary environmental cues to promote endogenous mechanisms of tissue repair. (Camelliti et al., 2004; Mahoney et al., 2016). In the event of ischemic injury and the resulting disruption of the local microenvironment of the infarcted myocardium, cardiac fibroblasts become activated to a myofibroblast state (Baum and Duffy, 2011; Dixon and Wigle, 2015; Figure 1). Myofibroblast activity drives maladaptive structural cardiac remodeling and fibrosis through dysregulation of ECM homeostasis and disruption of the local bioactive milieu, including growth factors and cytokines (Fedak et al., 2005a,b; Krenning et al., 2010; Dixon and Wigle, 2015). Open in a separate window FIGURE 1 Human cardiac fibroblast (left) compared to TGF- activated human cardiac myofibroblasts (right). Myofibroblasts are larger in cell size, have an increased number of cell RG3039 extensions, and increased cell extension length. Alpha smooth muscle actin (-SMA) expression and collagen production and deposition (collagen, yellow) are both increased in human cardiac myofibroblasts compared to human cardiac fibroblasts. Hoechst staining is used to visualize cell nuclei (nuclei, blue). Images were provided courtesy of Dr. Guoqi Teng, University of Calgary. Myofibroblast-Mediated Extracellular Matrix Remodeling Specifically, the infarcted myocardium undergoes a three-stage wound healing process: (1) inflammatory stage, (2) proliferative stage, and (3) maturation stage RG3039 REV7 (Figure 2). Initially, the inflammatory stage is characterized by cardiomyocyte and endothelial cell death, immune cell recruitment, and an increase in pro-inflammatory cytokines (Dobaczewski et al., 2010b; Shinde and Frangogiannis, 2014; Saxena and Frangogiannis, 2015). During this stage, cardiac fibroblasts assume a pro-inflammatory phenotype and contribute to inflammation via the production of various cytokines (IL-1, IL-1, IL-6, IL-8, and TNF-) (Kawaguchi et al., 2011; Fan et al., 2012; Shinde and Frangogiannis, 2014). Next, the proliferative stage is marked by cardiac fibroblast differentiation to a myofibroblast phenotype and migration to the region of infarcted myocardium (Shinde and Frangogiannis, 2014; Figure 2). This shift may be driven by an upregulation in transforming growth factor beta (TGF-), ED-A fibronectin, and mechanical stress (Serini et al., 1998; Lee et al., 1999; Vaughan et al., 2000; Tomasek et al., 2002; Zhao et al., 2007; Dobaczewski et al., 2010a; Shinde and Frangogiannis, 2014; Figure 1). Myofibroblasts are characterized by increased alpha-smooth muscle actin (-SMA) expression (Figure 1), which corresponds with increased contractility and manipulation of the surrounding ECM environment (Leslie et al., 1991; Arora and McCulloch, 1994; Hinz et al., 2001). Myofibroblasts also display altered matrix metalloproteinase (MMP) and tissue inhibitors of matrix metalloproteinases (TIMPs) production (Fedak et al., 2005b). The altered expression of these ECM-regulatory proteins results in the net deposition of type I collagen, along with other ECM proteins (Brown et al., 2005; Heymans et al., 2005). Finally, the purpose of the maturation stage is scar tissue formation, wherein increased ECM deposition is necessary to form.