Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation

Abstract

Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives.

Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration

“…Nonetheless, given the conflicting data available, the mechanisms responsible for the loss/acquisition of immunogenicity are not fully clarified yet. Further work is required to verify whether hiPSC-derived cell epigenetic memory represents an advantage or a real obstacle for clinical application for both autologous and allogeneic hiPSC derivatives [133]. Indeed, the cell's ability to "be invisible to the immune system" due to an attained or induced loss of immunogenicity may lead to an increase in tumorigenicity.…”

The Nexus of Stem Cell-Derived Beta-Cells and Genome Engineering

“…iPSCs have the attribute of being patientspecific, thereby avoiding, potentially, many of the immunogenic properties that allogeneic transplants hold. However, whether autologous iPSCbased therapies would escape immune recognition and destruction by a recipient's immune system is still an unanswered question that needs further investigation in long-term studies [36][37][38]. As the field progresses, combining iPSC technologies with genomic modification to ensure success in transplantation without the need for immunosuppression brings these types of therapies closer to a clinical reality.…”

Synthetic Biology in Cell and Organ Transplantation

“…Even syngeneic cells can be immunogenic, as shown in experiments with induced pluripotent stem cells (iPSCs) (Sackett et al 2016). A significant number of effective pharmacologic agents have been developed for the prevention of rejection responses (Allison 2016).…”