Abstract P1137: Combination Of Zebularine Treated Rat Bone Marrow Mesenchymal Stem Cells With 3d Collagen Scaffold Preserves Ventricular Remodeling In Rat Myocardial Infarction Model

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally due to immensely high morbidity and mortality ratio. The incidence of CVD, particularly myocardial infarction (MI), is expected to increase rapidly in the coming decades. MI causes the death of myocytes, which ultimately leads to heart failure. Advancements in medical and surgical treatments can only limit the disease progress but cannot improve the function of infarcted myocardium. Therefore, a promising treatment strategy for ischemic heart diseases is highly needed. Stem cell therapy holds great potential to regenerate the injured myocardium due to the self-renewal and differentiation potential of these cells. Among various types, mesenchymal stem cells (MSCs) are potential candidates for regenerating the damaged cardiac tissue due to their multi-lineage differentiation potential and ease of isolation. However, certain issues such as poor survival and engraftment can prevent them from fully restoring normal cardiac structure and function. The use of biomaterials provides suitable microenvironment to the cells to perform various biological functions, and can solve the poor cellular engraftment problem associated with cell transplantation alone. In this study, we used natural three dimensional (3D) collagen scaffold along with demethylating agent, zebularine, for in vivo transplantation in rat MI model. Treatment with zebularine is shown to enhance cardiac differentiation of MSCs. MSCs were isolated from rat bone marrow, characterized, seeded in collagen scaffold and treated with zebularine. Cytotoxicity analysis was performed to confirm the non-cytotoxic effect of the treatments, and gene and protein expression levels were analyzed using cardiac specific primers and antibodies, respectively. In vitro analysis revealed that treatment in the 3D environment significantly enhanced cardiac differentiation of MSCs both at gene and protein levels. For in vivo analysis, rat MI model was developed and zebularine treated MSC-seeded scaffold was transplanted and compared with the MI group, along with other groups in which only collagen scaffold and untreated MSC-seeded scaffold were transplanted. Echocardiographic analysis revealed enhanced functional improvement in zebularine treated MSC-seeded group as compared to the other groups. Histological analysis revealed tissue preservation, cardiac regeneration beneath the scaffold, reduction in the fibrotic scar and improvement in the ventricular wall thickness in the treated MSC group. This strategy is expected to overcome the problems associated with cell transplantation alone and to provide an effective therapeutic strategy for improved cardiac function.