Development of Immune Deficient FAH-knockout Miniature Pig

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Aug 29

PMID 36032112

Authors

Heng Zhao

Weijian Ye

Jianxiong Guo

Jiaoxiang Wang

Deling Jiao

Kaixiang Xu

Chang Yang

Shuhan Chen

Muhammad Ameen Jamal

Zhongbin Bai

Taiyun Wei

Jie Cai

Tien Dat Nguyen

Yubo Qing

Wenmin Cheng

Baoyu Jia

Honghui Li

Hong-Ye Zhao

Qingfeng Chen

Hong-Jiang Wei

Affiliations

Soon will be listed here.

Abstract

Human hepatocyte transplantation for liver disease treatment have been hampered by the lack of quality human hepatocytes. Pigs with their large body size, longevity and physiological similarities with human are appropriate animal models for the expansion of human hepatocytes. Here we report on the generation of RAG2IL2RγFAH (RGFKO) pigs CRISPR/Cas9 system and somatic cell nuclear transfer. We showed that thymic and splenic development in RGFKO pigs was impaired. V(D)J recombination processes were also inactivated. Consequently, RGFKO pigs had significantly reduced numbers of porcine T, B and NK cells. Moreover, due to the loss of FAH, porcine hepatocytes continuously undergo apoptosis and consequently suffer hepatic damage. Thus, RGFKO pigs are both immune deficient and constantly suffer liver injury in the absence of NTBC supplementation. These results suggest that RGFKO pigs have the potential to be engrafted with human hepatocytes without immune rejection, thereby allowing for large scale expansion of human hepatocytes.

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