Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models.

Akihiro Mori,Haruka Wada,Hideki Taniguchi,Takeshi Takahashi,Soichiro Murata,Tomomi Tadokoro,Tomoki Murata,Ken-Ichiro Seino,Nao Tashiro,Satoshi Okamoto,Ryo Otsuka

doi:10.3390/cells10020476

Abstract

Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) with a homozygous expression of human leukocyte antigen (HLA) class I heavy chain (NOG-HLA-A2Tg) mice. After the transplantation of HLA-A2 human hematopoietic stem cells into NOG-HLA-A2Tg, we succeeded in achieving alloimmune responses after the HLA-mismatched human-induced pluripotent stem cell (hiPSC)-derived liver-like tissue transplantation. This immune response was inhibited by administering tacrolimus. In this model, we reproduced allograft rejection after the human iPSC-derived liver-like tissue transplantation. Human tissue transplantation on the humanized mouse liver surface is a good model that can predict T-cell-mediated cellular rejection that may occur when organ transplantation is performed.

Highlights

Liver transplantation is a useful intervention for patients with liver disease; liver donor graft shortage is a severe problem worldwide [1,2]
We generated hepatic endoderm (HE), endothelial cells (EC), and mesenchymal cells (MC) from human-induced pluripotent stem cell (hiPSC), as described previously [12,13] (Figure 1a). These results showed that HE cells were HNF4α (Hepatocyte nuclear factor 4 alpha)positive, EC were CD31-positive, and MC were CD166-positive (Figure 1a)
We revealed the acute allograft rejection mediated by cytotoxic

Summary

Introduction

Liver transplantation is a useful intervention for patients with liver disease; liver donor graft shortage is a severe problem worldwide [1,2]. As an alternative to liver transplantation, hepatocyte transplantation has been studied [2,3]; the target diseases of this treatment are limited. The source of hepatocytes is limited; the liver graft shortage and liver transplantation problems remain unresolved. Only some of the cells are able to be differentiate from hiPSCs, making it difficult to generate a whole organ from hiPSCs. Recently, an organoid study has made great strides to reconstruct a complicated organ like the structure in vitro by coculturing several cells [8,9,10]. An organoid study has made great strides to reconstruct a complicated organ like the structure in vitro by coculturing several cells [8,9,10] This technology reconstructs normal tissues but, cancer tissues [8]. We reported that liver bud transplantation improved the survival rate of mice models with acute liver disease [13]

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