Abstract 18111: Engineered Cell Therapy With Embryonic Stem Cell-Derived Cardiomyocytes Encapsulated in Injectable Nanomatrix Gel Enhanced Engraftment and Promoted Cardiac Repair in Experimental Myocardial Infarction

Background: A significant barrier to the therapeutic use of stem cells is poor cell engraftment in vivo. To overcome this hurdle, studies have attempted to engineer stem cells using biomaterials. Particularly, injectable self-assembling nanomatrix gel has emerged as a highly promising biomaterial by providing a natural extracellular matrix-like microenvironment. Here, we evaluate the therapeutic potential of cardiomyocytes (CMs) derived from mouse embryonic stem cells (mESCs) encapsulated with injectable nanomatrix gel consisting of peptide amphiphiles incorporating cell adhesive ligand RGDS (PA-RGDS) on experimental myocardial infarction (MI). Methods and results: First, we examined the survival of CMs on RGDS. We cultured rat neonatal CMs on PA-RGDS for 7 days and found that higher than 90% of the CMs remained alive with well-defined CM structures as determined by live/dead and immuno stainings. Next, to test if PA-RGDS can increase the retention of CMs in the heart, we intramyocardially injected DiI (fluorescent probe)-labeled CMs into the uninjured hearts with or without PA-RGDS. Flow cytometry analysis with enzymatically digested heart tissues harvested at day 7 showed a ~3 fold higher rate of mESC-CM engraftment in the mice receiving CMs with PA-RGDS compared to those receiving only mESC-CMs (11.3% ± 0.4 vs 4.4% ± 0.2). Finally, we investigated the therapeutic effects of mESC-CMs with PA-RGDS on the MI in comparison with PBS control, CM alone, and PA-RGDS alone. Weekly echocardiography demonstrated that three groups (CM, PA-RGDS and CM+PA-RGDS) showed higher ejection fractions than the PBS group at week 2. However, in the CM or PA-RGDS alone groups, cardiac function was dramatically reduced between 3-4 weeks. In contrast, the CM+PA-RGDS group maintained cardiac function for up to 12 weeks. Confocal microscopic examination showed that injected CMs in PA-RGDS engrafted robustly in myocardium, formed clusters, integrated into host myocardium, and expressed representative CM proteins such as cTNT and MHC6/7. Conclusions: This study demonstrated that implantation of ESC-derived CMs encapsulated with PA-RGDS improves cell retention and cardiac function post-MI. This engineered cell therapy can develop into a novel option for treating MI.