Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

Treatment of common bile duct disorders such as biliary atresia or ischaemic strictures is limited to liver transplantation or hepatojejunostomy due to the lack of suitable tissue for surgical reconstruction. Here, we report a novel method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree and we explore the potential of bioengineered biliary tissue consisting of these extrahepatic cholangiocyte organoids (ECOs) and biodegradable scaffolds for transplantation and biliary reconstruction in vivo. ECOs closely correlate with primary cholangiocytes in terms of transcriptomic profile and functional properties (ALP, GGT). Following transplantation in immunocompromised mice ECOs self-organize into tubular structures expressing biliary markers (CK7). When seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary marker expression (CK7) and function (ALP, GGT). This bioengineered tissue can reconstruct the wall of the biliary tree (gallbladder) and rescue and extrahepatic biliary injury mouse model following transplantation. Furthermore, it can be fashioned into bioengineered ducts and replace the native common bile duct of immunocompromised mice, with no evidence of cholestasis or lumen occlusion up to one month after reconstruction. In conclusion, ECOs can successfully reconstruct the biliary tree following transplantation, providing proof-of-principle for organ regeneration using human primary cells expanded in vitro

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: unique clinical and human leukocyte antigen associations

Primary sclerosing cholangitis (PSC) is well characterized in European populations. We aimed to characterize clinical characteristics and human leukocyte antigen (HLA) associations in a population of European American, Hispanic, and African American PSC patients listed for liver transplantation (LT). Population-stratified demographic, clinical, and HLA data from 6767 LT registrants of the United Network for Organ Sharing who had a diagnosis of PSC (4.7% of the registrants) were compared to data from registrants with other diagnoses. Compared to European Americans and Hispanics, African Americans were significantly younger (46.6 \ub1 13.7, 42.3 \ub1 15.9, and 39.7 \ub1 13.1 years, respectively; P = 0.002) and were listed with a higher Model for End-Stage Liver Disease score (15.2 \ub1 7.5, 14.9 \ub1 7.6, and 18.1 \ub1 9.3, respectively; P = 0.001); they were also less frequently noted to have inflammatory bowel disease in comparison with European Americans (71.4% versus 60.5%, P < 0.01). In multivariate analysis, African origin was a significant factor associated with listing for LT with PSC (odds ratio with respect to European Americans = 1.325, 95% confidence interval = 1.221-1.438). HLA associations in European Americans, Hispanics, and African Americans with PSC versus alcoholic liver disease were detected for HLA-B8, HLA-DR13, and protective HLA-DR4. However, HLA-DR3, which is in linkage disequilibrium with HLA-B8, showed associations only in European Americans and Hispanics. In conclusion, African Americans with PSC who are listed for LT differ clinically from European Americans and Hispanics. The association with HLA-B8 but not HLA-DR3 in African Americans should make possible the refinement of the HLA associations in PSC