Abstract 13128: Engineered Three-Dimensional Vascularized Cardiac Muscle Construct for Myocardial Repair and Regeneration

Introduction:Functional bioengineered cardiac muscle constructs using human induced pluripotent stem cell (hiPSCs) derived cardiovascular cells have been proved to hold a great potential for myocardial infarct (MI) treatment. However, one of the major challenges to these approaches has been the inability to vascularize/perfuse the in vitro engineered tissue constructs. Strategies aiming at the improvement of neovascularization of engineered tissues are critical importance, and is one method of providing oxygen and nutrients to the cells contained in the biomaterial constructs. N-cadherin (CDH2), a cell adhesion protein widely expressed in heart, had been demonstrated to enhance angiogenesis and correlated with the efficacy of stem cells therapy for myocardial repair.Hypothesis:In this study, using a mouse MI model, we have investigated whether the reparative potency of hiPSC-derived cardiac myocytes (CMs) can be enhanced through overexpression of CDH2 on a three-dimensional (3D) prevascularized collagen cell carrier (CCC) scaffold.Methods:Prevascularized cardiac constructs (VCCs) were generated using hiPSC-derived endothelial (hiPSC-ECs), smooth muscle cells (hiPSC-SMCs), and either CDH2-overexpressing or wild-type CMs (hiPSC-CDH2-CMs/hiPSC-WT-CMs) on CCCs. MI was induced in severe combined immunodeficiency (SCID) mice through permanent coronary artery ligation. Next, the mice were treated with VCC. Animal groups included: MI heart treated with CDH2-VCC (hiPSC-CDH2-CMs); WT-VCC (hiPSC-WT-CMs); MI heart treated with cell-free CCC (MI+CCC); or with no CCC (MI group). Cardiac functions were evaluated by echocardiography, and the engraftment rate and infarct size were evaluated histologically.Results:In vivo, measurement of cardiac functions, such as left-ventricular ejection fraction (EF), fractional shortening (FS), infarct size, and cell engraftment rate at day 28 post MI, were significantly greater in the CDH2-VCC treatment MI group than in the WT-VCC treatment MI group, and in both cell-treatment groups compared with MI only group.Conclusions:The 3D prevascularized VCCs consisting of hiPSC-CDH2-CMs improve not only the engraftment but also the reparative potency of implanted CCC patch in the failing hearts.