Potential barriers to therapeutics utilizing pluripotent cell derivatives: Intrinsic immunogenicity of in vitro maintained and matured populations

The potential to develop into any tissue makes pluripotent stem cells (PSCs) one of the most promising sources for cellular therapeutics. However, numerous hurdles exist to their clinical applications, three of the most concerning include the inability to separate therapeutic population from heterogeneously differentiated cultures, the risk of teratoma formation from residual pluripotent cells, and immunologic rejection of engrafted cells. The recent development of induced PSCs has been proposed as a solution to the histocompatibility barrier. Theoretically, creation of patient-specific induced PSC lines would exhibit a complete histocompatibility antigen match. However, regardless of the PSC source, in vitro propagation and nonphysiologic differentiation may result in other, likely less powerful, mechanisms of immune rejection. In light of recent progress towards clinical application, this review focuses on two such potential immunologic mechanisms applicable to isogenic PSC derivates: namely, the immunogenicity of aberrant antigens resulting from long-term in vitro maintenance and alterations in immunologic properties due to rapid in vitro differentiation. These issues will be considered with attention to their relation to effector cells in the adult immune system. In addition, we highlight immunosuppressive approaches that could potentially address the immunogenicity of these proposed mechanisms.