Immune tolerance of human induced pluripotent stem cell-derived myogenic progenitor cells in humanized mice

ABSTRACT It is still unclear if immune responses will compromise the large scale utilization of cell therapies derived from human induced pluripotent stem cells (hiPSCs). To answer this question, we used humanized mouse models generated by the adoptive transfer of peripheral blood mononuclear cells (Hu-AT) or the co-transplantation of hematopoietic stem cells and human thymic tissue (Hu-BLT). Using these mice we evaluated the engraftment in skeletal muscle of myogenic cells either obtained directly from a muscle biopsy or differentiated from hiPSCs or fibroblasts. Our results showed that while allogeneic grafts were rejected and highly infiltrated with human T cells, engraftment of autologous cells was tolerated, indicating reprogramming and differentiation procedures are not immunogenic. We also observed that hiPSC-derived myogenic progenitors are not targeted by autologous T cells and natural killer (NK) cells in vitro. Overall, our findings suggest that hiPSC-derived myogenic progenitors will be tolerated in the presence of a competent human immune system. SIGNIFICANCE The immunogenicity of human iPSC-derived cells will strongly influence their use in regenerative medicine. This important feature has so far been mostly understudied given the necessity to have access to humanized mice reconstituted with an immune system autologous to iPSC-derived cells. Using two distinct mouse models we here provide evidences that human immune cell infiltration in skeletal muscle should not be used as the sole marker to predict immunogenicity. Indeed, we show that human iPSC-derived myogenic progenitors, similar to primary human myoblasts, induced autologous T cell infiltration yet without compromising engraftment. Our study provides essential pre-clinical data supporting the usage of human iPSC-derived myogenic progenitor cells.