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- Title
Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells.
- Authors
Sullivan, Kelly Elizabeth; Quinn, Kyle Patrick; Tang, Katherine Michele; Georgakoudi, Irene; Black III, Lauren Deems
- Abstract
Introduction While stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. There is a need to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment impact 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 following myocardial infarction. Methods Mechanical and compositional changes to the decellularized infarcted myocardium were characterized to understand how the extracellular environment, specifically, was altered as a function of time following 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. Lastly, the paracrine secretome was characterized as a function of matrix remodeling through gene and protein expression and conditioned media studies. Results The decellularized infarct tissue revealed significant alterations in both the mechanical and compositional properties of the ECM with remodeling time post-MI. This altered microenvironment dynamically regulates the potential for early cardiac differentiation. While Nkx2.5 expression is limited in the presence of chronically remodeled matrix of increased stiffness, GATA4 expression is enhanced. In addition, the remodeled matrix promotes the expression of several pro-angiogenic, pro-survival, anti-fibrotic 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. Conclusions This study demonstrated that decellularization of diseased tissue allows for the exclusive analysis of the remodeled matrix and its ability to significantly influence 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 ultimately reduce the prevalence and severity of heart failure.
- Subjects
STEM cells; BLOOD circulation disorders; CORONARY disease; NECROSIS; INFARCTION
- Publication
Stem Cell Research & Therapy, 2014, Vol 5, Issue 1, p1
- ISSN
1757-6512
- Publication type
Article
- DOI
10.1186/scrt403