Regional differences in human biliary tissues and corresponding in vitro derived organoids

Casey A Rimland, Samantha G Tilson, Carola M Morell, Rute A Tomaz, Wei-Yu Lu, Simone E Adams, Nikitas Georgakopoulos, Francisco Otaizo-Carrasquero, Timothy G Myers, John R Ferdinand, Richard L Gieseck, Fotios Sampaziotis, Olivia C Tysoe, Brandon Wesley, Daniele Muraro, Gabriel C Oniscu, Nicholas Rf Hannan, Stuart J Forbes, Kourosh Saeb-Parsy, Thomas A WynnLudovic Vallier

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BACKGROUND: Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (Extrahepatic Bile Ducts or EHBDs) or inside the liver (Intrahepatic bile ducts or IHBDs). These organoids share many characteristics including the expression of cholangiocyte markers such as KRT19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown.

METHODS/RESULTS: Organoids were derived from human gallbladder, common bile duct, pancreatic duct and intrahepatic bile ducts using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers LGR5/PROM1 and ductal markers KRT19/KRT7. However, RNA-sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, downregulation of biliary markers and upregulation of cell cycle genes was observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling and only IHBD were able to express a low-level of hepatocyte markers under differentiation conditions.

CONCLUSIONS: Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify new targets for therapeutic development.

Original languageEnglish
JournalHepatology
Early online date29 Mar 2020
DOIs
Publication statusE-pub ahead of print - 29 Mar 2020

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