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

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

Abstract

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.

Citation

Rimland, C. A., Tilson, S. G., Morell, C. M., Tomaz, R. A., Lu, W.-Y., Adams, S. E., Georgakopoulos, N., Otaizo-Carrasquero, F., Myers, T. G., Ferdinand, J. R., Gieseck, R. L., Sampaziotis, F., Tysoe, O. C., Wesley, B., Muraro, D., Oniscu, G. C., Hannan, N. R., Forbes, S. J., Saeb-Parsy, K., Wynn, T. A., & Vallier, L. (2021). Regional differences in human biliary tissues and corresponding in vitro derived organoids. Hepatology, 73(1), 247-267. https://doi.org/10.1002/hep.31252

• Journal Article Type: Article
• Acceptance Date: Mar 9, 2020
• Online Publication Date: Mar 29, 2020
• Publication Date: 2021-01
• Deposit Date: Jun 8, 2020
• Publicly Available Date: Mar 30, 2021
• Journal: Hepatology
• Print ISSN: 0270-9139
• Electronic ISSN: 1527-3350
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 73
• Issue: 1
• Pages: 247-267
• DOI: https://doi.org/10.1002/hep.31252
• Keywords: Hepatology
• Public URL: https://nottingham-repository.worktribe.com/output/4607471
• Publisher URL: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31252