Generation of immunocompatible cardiac myocytes for heart repair

Abstract

Background Repair of myocardia with stem cell derived cardiomyocytes (SC-CM) is becoming increasingly realistic, although major obstacles still exist, including immunorejection of the grafts. Expression of MHC class I (MHC-I) molecules by grafted cells is the main reason for rejection. Downregulation of MHC molecules in SC-CM should reduce the immunogenicity of these cells. Results Cardiomyocytes were derived from mouse embryonic SC (CorAt) in which puromycin resistance gene was driven by a cardiac-specific promoter. CorAt formed beating cardiomyocytes and expressed cardiac specific proteins. The effect of inflammatory stimuli on the expression of MHC-I molecules was mimicked by IFN-gamma treatment. MHC-I expression was reduced by RNA interference against beta2-microglobulin (light chain) as measured by qPCR. Transduction of CorAt with anti-beta2-microglobulin shRNA lentivirus led to a lowered activation of cognate T-cells when MHC-I downregulated CorAt were used as targets. Similar results were obtained with W19 fibroblasts, confirming that analogous strategy can be used for a variety of cells. Conclusions The CorAT cells were effective in the repair of ischemic myocardia of syngeneic mice. Making these cells immunocompatible with allo- or xenogeneic recipients offers a reliable source of ESC-CM for small rodents and can be extended to ESC of large mammals for human heart repair.