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 Wynn; Ludovic Vallier

doi:10.1002/hep.31252

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 journal › Article › peer-review

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.

Original language	English
Journal	Hepatology
Early online date	29 Mar 2020
DOIs	https://doi.org/10.1002/hep.31252
Publication status	E-pub ahead of print - 29 Mar 2020

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10.1002/hep.31252Licence: Creative Commons: Attribution (CC-BY)

Regional differences in human biliary tissues and corresponding in vitro derived organoidsAccepted author manuscript, 10 MBLicence: Creative Commons: Attribution (CC-BY)

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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., ... Vallier, L. (2020). Regional differences in human biliary tissues and corresponding in vitro derived organoids. Hepatology. Advance online publication. https://doi.org/10.1002/hep.31252

@article{0947b2caa6104bebb15f8c1b4272899a,

title = "Regional differences in human biliary tissues and corresponding in vitro derived organoids",

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.",

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

year = "2020",

month = mar,

day = "29",

doi = "10.1002/hep.31252",

language = "English",

journal = "Hepatology",

issn = "1527-3350",

publisher = "Wiley",

}

Rimland, CA, Tilson, SG, Morell, CM, Tomaz, RA, Lu, W-Y, Adams, SE, Georgakopoulos, N, Otaizo-Carrasquero, F, Myers, TG, Ferdinand, JR, Gieseck, RL, Sampaziotis, F, Tysoe, OC, Wesley, B, Muraro, D, Oniscu, GC, Hannan, NR, Forbes, SJ, Saeb-Parsy, K, Wynn, TA & Vallier, L 2020, 'Regional differences in human biliary tissues and corresponding in vitro derived organoids', Hepatology. https://doi.org/10.1002/hep.31252

TY - JOUR

T1 - Regional differences in human biliary tissues and corresponding in vitro derived organoids

AU - Rimland, Casey A

AU - Tilson, Samantha G

AU - Morell, Carola M

AU - Tomaz, Rute A

AU - Lu, Wei-Yu

AU - Adams, Simone E

AU - Georgakopoulos, Nikitas

AU - Otaizo-Carrasquero, Francisco

AU - Myers, Timothy G

AU - Ferdinand, John R

AU - Gieseck, Richard L

AU - Sampaziotis, Fotios

AU - Tysoe, Olivia C

AU - Wesley, Brandon

AU - Muraro, Daniele

AU - Oniscu, Gabriel C

AU - Hannan, Nicholas Rf

AU - Forbes, Stuart J

AU - Saeb-Parsy, Kourosh

AU - Wynn, Thomas A

AU - Vallier, Ludovic

PY - 2020/3/29

Y1 - 2020/3/29

N2 - 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.

AB - 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.

U2 - 10.1002/hep.31252

DO - 10.1002/hep.31252

M3 - Article

C2 - 32222998

SN - 1527-3350

JO - Hepatology

JF - Hepatology

ER -

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

Abstract

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