Immunogenicity of Cardiomyocytes Derived from Induced Pluripotent Stem Cells

Myocardial cell replacement therapy has become an attractive solution for myocardial repair in order to prevent heart failure. Transplantation of human cardiomyocytes (CMs), generated from induced pluripotent stem cells (iPSC), can result in optimal remuscularization of the scar, potentially circumventing the need for immune suppression if given in an autologous manner. Research regarding immunogenicity of iPSCs is inconsistent; while some articles describe iPS cells as immune privileged others show that iPSCs and iPSCs derivatives can elicit immune response.

We aimed to assess the potential immunogenicity of iPSC derived CMs (iPSC-CMs). To this end we produced a mouse iPS cell line from C57BL/6 mice, which stably expresses GFP in order to allow us to track the cells in the mouse heart after transplantation. We then utilized the hanging drop method to induce the differentiation of the mouse iPSCs into functional cardiomyocytes. The iPSC-CMs were then engrafted to the left-ventricular apex of C57BL/6 mice for syngeneic transplantation, and into hearts of ICR mice as an allogeneic transplantation model. The injected hearts were harvested after a period of two weeks. Images of heart section slides were acquired, and morphometric analysis was performed in order to examine graft survival, composition, and size. Examination of the immune response in the injection sites was performed by immunostaining targeting T cell specific markers. Allogeneic transplantations resulted in cell death and severe immune rejection (CD4⁺ and CD8⁺ T cells infiltration) as opposed to syngeneic transplantation where significant cell survival was observed 14 days post-transplantation with limited immune cell infiltration.

Our results reinforce the hypothesis that transplantation of syngeneic iPSCs derived CMs does not elicit immune response. This suggests that autologous iPSC-CMs are not immunogenic and may be utilized for future regenerative medicine applications avoiding the need for immunosuppression.