Human iPSC-liver organoid transplant reduces fibrosis by immunomodulation

Donor organ shortage for transplant is a serious problem worldwide. Organoid culture technology, which allows the generation of complex organs from stem cells, provides a potential solution. We previously reported in vivo vascularization of human induced pluripotent stem cell (hiPSC)-derived liver buds (LBs) and subsequent improved survival of recipient mice with acute liver failure1,2. Here, we show that mid-gestational fetal liver tissue can generate de novo liver when grafted onto the surface of host livers and improve survival and liver functions in a model of liver failure. Next, we created complex fetal liver-like organoids (LOs) by a fusion of hiPSC-LBs to induce static cell-cell interactions, and show that these contain hepatocytes, vasculature, and bile duct after transplantation. Fused hiPSC-LOs show superior liver functions compared to hiPSC-LBs and improve survival and functions of liver failure model upon transplantation. Finally, transplant of fused hiPSC-LOs ameliorates liver fibrosis, a symptom of liver cirrhosis which leads to organ dysfunction, through their immunomodulatory effects especially on macrophage polarization that plays an important role in the regulation of liver fibrosis3–5. Taken together, our results suggest that hiPSC-LO transplant could be a promising therapeutic option for liver failure patients in the near future Transcriptome profiling of human iPSC-derived liver buds (hiPSC-LB) and hiPSC-liver organoids