Background: Heart failure is one of the most promising targets for cell replacement therapy with induced pluripotent stem cells (iPSCs). Since the iPSCs can be derived in a patient-specific manner they could avoid the issue of immune rejection because of their autologous nature. A recent study (Zhao, Nature 2011) challenged this assumption by revealing unexpected immune rejection of teratomas derived from undifferentiated syngeneic murine iPSCs. This immunogenicity was thought to result from expression of new antigens following reprogramming.
Aims: To assess the immunogenicity of differentiated iPSCs progeny (iPSCs-derived cardiomyocytes, iPSC-CMs) following transplantation into the myocardium of syngeneic and allogeneic recipients.
Methods and Results: We utilized a C57BL/6 mouse iPSC line, generated by retroviral transduction with OCT4, SOX2, KLF4, and c-Myc that also expresses DsRed. Injection of undifferentiated iPSCs (5x106) into syngeneic (C57BL/6) mice resulted in generation of teratomas in only 1/8 of the animals with the rest rejected.
The iPSCs were coaxed to differentiate into myocytes, which displayed typical cardiomyocyte gene expression and structural properties. The iPSC-CMs were then engrafted into the left ventricle of syngeneic (C57BL/6) or allogeneic (ICR) mice-recipients. Graft survival and immune infiltration was analyzed 14 days later. Immunostaining revealed only limited T-cells infiltration in association with the syngeneic iPSC-CMs grafts. In contrast, there was extensive CD4+ and CD8+ T cells infiltration in the hearts of allogeneic recipient mice. Consequently, a higher number of cardiomyocytes survived in the syngeneic grafts, as reflected by higher intensities of DsRed expression (10-fold) when compared to the allografts.
Conclusions: Our findings support the idea that cardiomyocytes generated from autologous iPSCs could be applied for future myocardial cell replacement therapy without eliciting immune rejection. This matter is of substantial relevance when considering the potential utility of iPSCs for regenerative medicine.
