Human iPSC-derived renal cells change their immunogenic properties during maturation: Implications for regenerative therapies

Abstract

Therapeutic success of human induced pluripotent stem cell (hiPSC)-based therapies critically depends on immunological compatibility of the hiPSC-derived transplant. As grafted hiPSC-derived cells are often immature, we hypothesized that their immunologic properties may change due to post-grafting maturation. Subsequently, this will affect their interaction with the host immune system and may compromise graft tolerance. In the present study allogeneic and autologous cellular immunity of primary cells, therof reprogrammed hiPSC, hiPSC-derived progenitor and terminally differentiated cells was investigated in vitro by using renal cells as a model system. In contrast to allogeneic primary cells, hiPSC-derived early renal progenitors and mature renal epithelial cells were both tolerated not only by autologous but also by allogeneic T cells. These immune-privileged properties resulted from active immune-modulation and low immune visibility, which declined during the process of cell maturation. However, autologous and allogeneic natural killer (NK) cell responses were not suppressed by hiPSC-derived renal cells and efficiently changed NK cell activation status. These findings clearly show a dynamic stage-specific dependency of autologous and allogeneic T- and NK cell responses to the hiPSC-derived renal cell lineage with consequences for effective cell therapies. The study suggests that hiPSC-derived early progenitors may provide advantageous immune suppressive properties when applied in cell therapy. The data furthermore indicate a need to suppress NK cell activation in allogeneic as well as autologous settings.