Abstract
IntroductionAlthough stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. A need exists to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment affect their ability to regenerate the necrotic tissue. In this study, we assessed both differentiation capacity and paracrine signaling as a function of extracellular matrix remodeling after myocardial infarction.MethodsMechanical and compositional changes to the decellularized infarcted myocardium were characterized to understand how the extracellular environment, specifically, was altered as a function of time after coronary artery ligation in Sprague–Dawley rats. These alterations were first modeled in a polyacrylamide gel system to understand how the variables of composition and stiffness drive mesenchymal stem cell differentiation towards a cardiac lineage. Finally, the paracrine secretome was characterized as a function of matrix remodeling through gene and protein expression and conditioned media studies.ResultsThe decellularized infarct tissue revealed significant alterations in both the mechanical and compositional properties of the ECM with remodeling following infarction. This altered microenvironment dynamically regulates the potential for early cardiac differentiation. Whereas Nkx2.5 expression is limited in the presence of chronic remodeled matrix of increased stiffness, GATA4 expression is enhanced. In addition, the remodeled matrix promotes the expression of several proangiogenic, prosurvival, antifibrotic, and immunomodulatory growth factors. In particular, an increase in HGF and SDF1 expression and secretion by mesenchymal stem cells can rescue oxidatively stressed cardiomyocytes in vitro.ConclusionsThis study demonstrated that decellularization of diseased tissue allows for the exclusive analysis of the remodeled matrix and its ability to influence significantly the cellular phenotype. Characterization of cell fate as a function of myocardial remodeling following infarction is critical in developing the ideal strategy for cell implantation to maximize tissue regeneration and to ultimately reduce the prevalence and severity of heart failure.
Highlights
Stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application
We investigated alterations in paracrine signaling in response to infarct matrix and determined that the late, remodeled matrix significantly enhances the expression of several growth factors, including hepatocyte growth factor (HGF) and stromal cell-derived factor 1 (SDF1)
At 1 week post-myocardial infarction (MI), the scar matrix increases significantly (P < 0.05). 2 and 4 weeks post-MI, the tissue is significantly stiffer than both the healthy and 1 week infarct matrix (P < 0.05) (Figure 1C). This increase in stiffness may be related to a significant increase in the number of small diameter fibers deposited throughout the tissue after MI, as revealed by Second harmonic generation (SHG) imaging (Figure 1B)
Summary
Stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. A need exists to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment affect their ability to regenerate the necrotic tissue. We assessed both differentiation capacity and paracrine signaling as a function of extracellular matrix remodeling after myocardial infarction. The most commonly studied approach is stem cell therapy, which strives to regenerate the necrotic myocardium with multi- or pluripotent stem cells capable of rescuing the organ through their differentiation toward contractile cardiomyocytes or proangiogenic and prosurvival paracrine signaling to native cells of the injured heart [2,3,4,5,6]. The MSC secretome after implantation is poorly understood, and to harness its full potential, we must characterize what factors within the infarct microenvironment drive its expression profile [17]
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