ABSTRACT
Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.
Subject(s)
Bile Duct Diseases/therapy , Bile Ducts, Intrahepatic/physiology , Bile Ducts/cytology , Cell- and Tissue-Based Therapy , Epithelial Cells/cytology , Organoids/transplantation , Animals , Bile , Bile Ducts/physiology , Bile Ducts, Intrahepatic/cytology , Common Bile Duct/cytology , Epithelial Cells/physiology , Gallbladder/cytology , Gene Expression Regulation , Humans , Liver/physiology , Liver Transplantation , Mesenchymal Stem Cell Transplantation , Mice , Organoids/physiology , RNA-Seq , Tissue and Organ Procurement , TranscriptomeABSTRACT
Increased serum levels of IgG4 have been reported in 9%-15% of patients with primary sclerosing cholangitis (PSC); it is not clear whether this increase contributes to pathogenesis. We performed genetic analyses of the HLA complex in patients with PSC from Norway, Sweden, and from the United States. We found an association between levels of IgG4 above the upper reference limit and specific HLA haplotypes. These patients had a significantly lower frequency of the strongest PSC risk factor, HLA-B*08, than patients without increased IgG4, and significantly higher frequencies of HLA-B*07 and HLA-DRB1*15. HLA genotype therefore might affect the serum concentration of IgG4, and increased IgG4 might be a marker of a distinct phenotype of PSC.