Humanized mice reveal an essential role for human hepatocytes in the development of the liver immune system

Jinglong Guo,Yanhong Shan,Feng Wang,Ge Zheng,Xue Wang,Chang Shu,Jin He,Yang Li,Zheng Hu,Yong-Guang Yang

doi:10.1038/s41419-018-0720-9

Abstract

The liver is an immunological organ with a distinct immune cell profile. Although the composition and function of liver immune cells have been widely investigated, the mechanisms regulating the development and homeostasis of the specialized immune system, especially in humans, remain largely unknown. Herein, we address this question in humanized mice (hu-mice) that were constructed by transplantation of human fetal thymus and CD34+ hematopoietic stem/progenitor cells in immunodeficient mice with or without autologous human hepatocyte engraftment. Although the levels of human immune cell reconstitution in peripheral blood and spleen were comparable between hu-mice with and without human hepatocyte engraftment, the former group showed that human immune cell reconstitution in the liver was significantly improved. Notably, human immune cells, including Kupffer cells, dendritic cells and natural killer cells, were shown to be closely colocalized with human hepatocytes in the liver. Human hepatocytes engrafted in the mouse liver were found to produce IL-3, IL-15, GM-CSF, M-CSF, MCP-1, CXCL-1 and CXCL-10, which are known to be important for immune cell development, differentiation, tissue migration and retention, and have no or poor cross-reaction between humans and mice. Furthermore, human hepatocytes were able to support human immune cell survival and expansion in an in vitro co-culture assay. This study demonstrates an essential role for hepatocytes in the development and maintenance of the liver immune cell profile. The hu-mouse model with human autologous immune cell and hepatocyte reconstitution has potential for use in studies of the pathogenesis of liver immune disorders such as hepatotropic virus infections.

Highlights

The liver is an important organ consisting of a large number and unique populations of immune cells
The liver is populated with a high proportion of innate immune cells including natural killer (NK) cells, NK-like T cells, Kupffer cells and dendritic cells (DCs), which play important roles in local immune
The liver is populated with a high proportion of innate immune cells, including NK cells, NK-like T cells, Kupffer cells and DCs, forming an liver-specific immune network that is important in liver regeneration, local immune surveillance and immunopathogenesis[1,2,3,4]

Summary

Introduction

The liver is an important organ consisting of a large number and unique populations of immune cells. We have previously shown that immunodeficient mice receiving cotransplantation of human fetal thymic tissue (FTHY) and CD34+ hematopoietic stem/progenitor cells (HSPCs) develop a robust human immune system[22,23]. These humanized mice (hu-mice; known as BLT humice24) have been demonstrated to develop functional human immune cells and secondary lymphoid organs, and widely used to assess human immune responses in vivo under physiological or diseased conditions[25,26], their tissue-specific immune reconstitution has not been explored well. This study provides a useful protocol for constructing hu-mice with improved liver-specific immunity, and direct evidence for an important role for hepatocytes in the development of the specialized human immune system in the liver

Methods

Results

Conclusion