Immunogenicity of In Vitro Maintained and Matured Populations: Potential Barriers to Engraftment of Human Pluripotent Stem Cell Derivatives

Abstract

The potential to develop into any cell type makes human pluripotent stem cells (hPSCs) one of the most promising sources for regenerative treatments. Hurdles to their clinical applications include i) formation of heterogeneously differentiated cultures, ii) the risk of teratoma formation from residual undifferentiated cells, and iii) immune rejection of engrafted cells. The recent production of human isogenic (genetically identical) induced PSCs (hiPSCs) has been proposed as a “solution” to the histocompatibility barrier. In theory, differentiated cells derived from patient-specific hiPSC lines should be histocompatible to their donor/recipient. However, propagation, maintenance, and non-physiologic differentiation of hPSCs in vitro may produce other, likely less powerful, immune responses. In light of recent progress towards the clinical application of hPSCs, this review focuses on two antigen presentation phenomena that may lead to rejection of isogenic hPSC derivates: namely, the expression of aberrant antigens as a result of long-term in vitro maintenance conditions or incomplete somatic cell reprogramming, and the unbalanced presentation of receptors and ligands involved in immune recognition due to accelerated differentiation. Finally, we discuss immunosuppressive approaches that could potentially address these immunological concerns.

Path to the Clinic: Assessment of iPSC-Based Cell Therapies In Vivo in a Nonhuman Primate Model

“…This phenomenon might be due to residual pluripotent gene expression in the tumors derived from autologous iPSCs, as described (Dhodapkar et al, 2010; Tang et al, 2013). However, we did not detect residual OCT4 expression in teratoma tissues despite ongoing lymphocytic infiltration.…”

“…However, the central nervous system is an immunologically protected and unique environment. Therefore, there is still a question about immunogenicity and tumorigenicity of iPSCs and their differentiated derivates when they are grafted into immunocompetent sites (Lee et al, 2013; Tang et al, 2013). Hence, there is a need to assess the safety and efficiency of iPSC-based therapies in a clinically relevant model (Kaneko and Yamanaka, 2013).…”

“…However, we did not detect residual OCT4 expression in teratoma tissues despite ongoing lymphocytic infiltration. It is also possible that NK-mediated rejection of PSCs but not of differentiated cells occurred due to low MHC class I expression on PSCs (Atoui and Chiu, 2012; Tang et al, 2013). In this study, we also found that MHC class I was not expressed on undifferentiated RhiPSCs, but was re-expressed during differentiation to RhiPSC-SCs.…”

Overcoming immunological barriers in regenerative medicine

“…A few studies have suggested that iPSC-derived cells can be immunogenic even when donor and recipient are genetically identical 98–100 . This may be due to retention of developmental antigens, acquisition of xenogenic epitopes, or expression of aberrant antigens over the course of long-term cultures used to generate iPSCs and differentiated cells 101,102 . Nonphysiologic in vitro differentiation can also alter the expression of molecules involved in immune recognition in a way that would trigger immune system reactions against the cells after transplantation, such as NK cell–mediated killing of cells expressing low levels of self MHC class I molecules 101 .…”

“…This may be due to retention of developmental antigens, acquisition of xenogenic epitopes, or expression of aberrant antigens over the course of long-term cultures used to generate iPSCs and differentiated cells 101,102 . Nonphysiologic in vitro differentiation can also alter the expression of molecules involved in immune recognition in a way that would trigger immune system reactions against the cells after transplantation, such as NK cell–mediated killing of cells expressing low levels of self MHC class I molecules 101 . Possible solutions to these problems include the development of mild immunosuppressive regimens (e.g., monoclonal antibodies targeting NK cells and/or T cell subsets) sufficient to induce tolerance to autologous iPSC-derived cells.…”