Genetic engineering drives the breakthrough of pig models in liver disease research

Abstract

Compared with the widely used rodents, pigs are anatomically, physiologically, and genetically more similar to humans, making them high-quality models for the study of liver diseases. Here, we review the latest research progress on pigs as a model of human liver disease, including methods for establishing them and their advantages in studying cystic fibrosis liver disease, acute liver failure, liver regeneration, non-alcoholic fatty liver disease, liver tumors, and xenotransplantation. We also emphasize the importance of genetic engineering techniques, mainly the CRISPR/Cas9 system, which has greatly enhanced the utility of porcine models as a tool for substantially advancing liver disease research. Genetic engineering is expected to propel the pig as one of the irreplaceable animal models for future biomedical research.

Keywords: Animal model; CRISPR/Cas9; Genetic engineering; Liver disease; Pig; Xenogeneic liver transplantation.

Fig. 1

The workflow for obtaining gene-edited pigs for xenotransplantation using the CRISPR/Cas9 technology. Abbreviations: α-1,3GT, alpha-1,3-galactosyltransferase; αGal, alpha-galactose; β-4GALNT2, beta-1,4-N-acetylg alactosaminyltransferase 2; CMAH, cytidine monophosphate-N-acetylneuraminic acid hydroxylase; MAC, membrane attack complex; NK, natural killer; NKG2D, natural killer group 2 member D; sgRNA, single-guide RNA.

Fig. 2

Summary of liver disease models in pigs. Abbreviations: α-1,3GT, alpha-1,3-galactosyltransferase; ALB, albumin; ALOX12, arachidonate 12-lipoxygenase; ARID1A, AT-rich interaction domain 1A; β-4GALNT2, beta-1,4-N-acetylg alactosaminyltransferase 2; CFTR, cystic fibrosis transmembrane conductance regulator; CMAH, cytidine monophosphate-N-acetylneuraminic acid hydroxylase; FAH, fumarylacetoacetate hydrolase; GIPR, glucose-dependent insulinotropic polypeptide receptor; hIAPP, human islet amyloid polypeptide; KRAS, Kirsten rat sarcoma viral oncogene homologue; MASH, metabolic dysfunction-associated steatohepatitis; MC4R, melanocortin 4 receptor; PERV, porcine endogenous retrovirus; PNPLA3, patatin like phospholipase domain-containing protein 3.