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Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases. RNA-Seq

ABSTRACT: Although providing promising and unique tools for studying cholangiocytes, current tissue-derived cholangiocyte-organoid systems do not recapitulate the complex architecture of the intrahepatic bile ducts in vitro. Here, we report a new method for creating branching cholangiocyte organoids (BRCO) from human adult tissue to study the intrahepatic biliary tree and diseases. BRCOs self-organize into large complex tubular structures, while closely resembling primary cholangiocytes on a transcriptomic and functional level. They are capable of mimicking branching bile duct development as well as being used for studying diseases in which the biliary tree does not develop properly (Alagille Syndrome). Furthermore, we deliver evidence that our culture method allows for formation of complex cholangiocyte cancer (cholangiocarcinoma, CCA) organoids. These branching CCA organoids resemble the primary tumor more closely compared to previously published protocols as well as showing unique tumor-specific drug responses. In conclusion, our culture method allows for creation of novel (malignant) cholangiocyte-organoids to study the intrahepatic bile ducts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179599 | GEO | 2022/05/04

REPOSITORIES: GEO

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Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases. scRNA-Seq

Project description:Although providing promising and unique tools for studying cholangiocytes, current tissue-derived cholangiocyte-organoid systems do not recapitulate the complex architecture of the intrahepatic bile ducts in vitro. Here, we report a new method for creating branching cholangiocyte organoids (BRCO) from human adult tissue to study the intrahepatic biliary tree and diseases. BRCOs self-organize into large complex tubular structures, while closely resembling primary cholangiocytes on a transcriptomic and functional level. They are capable of mimicking branching bile duct development as well as being used for studying diseases in which the biliary tree does not develop properly (Alagille Syndrome). Furthermore, we deliver evidence that our culture method allows for formation of complex cholangiocyte cancer (cholangiocarcinoma, CCA) organoids. These branching CCA organoids resemble the primary tumor more closely compared to previously published protocols as well as showing unique tumor-specific drug responses. In conclusion, our culture method allows for creation of novel (malignant) cholangiocyte-organoids to study the intrahepatic bile ducts.

2022-05-04 | GSE179597 | GEO

Proteome of human branching and non-branching cholangiocyte organoids

Project description:Current model systems for studying intrahepatic biliary disease fail to recapitulate the architecture of intrahepatic bile ducts. Organoids from intrahepatic cholangiocytes can with a new culture method grow with a branching pattern resembling the structure of intrahepatic bile ducts. This dataset contains data from samples of these organoids and from control organoids cultured without this technique. Culture have been performed using isotope labeled amino acids to help distinguish cell derived proteins from the basement membrane extract used as a culture substrate for the organoids.

2022-05-09 | PXD028532 | Pride

Comparison of extrahepatic cholangiocyte organoids and freshly isolated common bile duct cholangiocytes

Project description:Despite the impact of bile duct disorders, treatment options remain very limited. Poor access to biliary tissue and restrictions in long-term culture or significant expansion of primary cholangiocytes have posed major challenges for research in the field. These limitations have so far precluded large scale experiments such as transcriptomic and genome-wide analyses which are urgently needed to better understand biliary physiology and pathophysiology. To address this issue, we have developed a novel system for the isolation and propagation of primary cholangiocytes from the extrahepatic bile ducts. The resulting Extrahepatic Cholangiocyte Organoids (ECOs) maintain their genetic stability, transcriptomic profile and function over long term culture and are compatible with regenerative medicine applications such as biliary reconstruction. We established a novel protocol for the isolation and propagation of primary cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs). The aim of this experiment was to provide in depth characterisation of the transcriptome of ECOs during long term culture. We compare the transcriptome of ECOs cultured for 1 passage (P1), 10 passages (P10) and 20 passages (P20) with freshly isolated primary cholangiocytes from the common bile duct. Embryonic Stem Cells (ES) cells are used as a negative control=

2017-07-04 | E-MTAB-4591 | biostudies-arrayexpress

Transcription profiling of undifferentiated human extrahepatic cholangiocyte organoids (ECOs)

Project description:3D cell culture systems (organoids), cultured from extrahepatic bile duct biopsies, resemble biliary epthelium (cholangiocytes) upon culture according to the protocol previously established for culturing intrahepatic cholangiocyte organoids from liver biopsies (Huch et al. Cell 2015). These extrahepatic cholangiocyte organoids (ECOs) in Canonical-Wnt culture conditions maintain their genetic stability, and transcription profile and can be maintained and propagated during long periods of culturing while still maintaining their functional properties. The data presented in this ArrayExpress submission contained micro array results of 3 different ECO lines that were analyzed for their functional cholangiocyte ion-channels, involved in secreting a protective bicarbonate layer. It was shown that these data closely resemble the expression profile of intrahepatic cholangiocyte organoids (ICOs) as described by our group. Results of the ICOs are deposited in the EMBL-EBI ArrayExpress repository under number E-MTAB-9044.

2021-01-01 | E-MTAB-9807 | biostudies-arrayexpress

Transcription profiling of undifferentiated human liver-derived intrahepatic cholangiocyte organoids (ICOs)

Project description:3D cell culture systems (organoids), cultured from liver biopsies, resemble biliary epthelium (cholangiocytes) upon culture. These intrahepatic cholangiocyte organoids (ICOs) maintain their gentic stability, transcription profile and can be maintained propagated during long periods of culturing while still maintaining their functional properties. The data presented in this ArrayExpress submission contained micro array results of 6 from 15 different ICO lines that were analyzed for their functional cholangiocyte ion-channels, involved in secreting a protective bicarbonate layer. It was shown that these data closely resemble the expression profiles of extrahepatic cholangiocyte organoids (ECOs), previously described by Sampaziotis et al. and deposited in the EMBL-EBI ArrayExpress repository (E-MTAB-4591)

2020-07-31 | E-MTAB-9044 | biostudies-arrayexpress

Distinct Phenotypes of Human Intrahepatic and Extrahepatic Bile duct Organoids and their Applications for Biliary Disease Modeling

Project description:Bile draining by the bile duct system is paramount for good liver function. Diseases which compromise the integrity of the biliary tree are common and often life-threatening. Both intrahepatic and extrahepatic bile ducts contain distinct (stem) cell niches which are important for bile duct homeostasis and repair. A detailed characterization of the cell populations in the extrahepatic bile ducts has been lacking due to the inability of cell culture propagation. The aim of this study was to expand extrahepatic bile duct stem cells using the organoid culture system developed for intrahepatic bile duct cells. Extrahepatic bile duct (eBD)-organoids and intrahepatic (iBD) liver-derived organoids were initiated from paired biopsies of human common bile duct and liver tissue. Organoids of both origins were characterized on the basis of morphology and growth characteristics, gene and protein expression profiles, and their differentiation capacity towards mature cholangiocytes and hepatocytes. Although eBD organoids were very similar to iBD liver organoids, some differences in growth rate, organoid size and gene and protein expression were found. More strikingly, although both organoids could be differentiated towards a mature cholangiocyte phenotype, only iBD organoids can be directed to a mature hepatocyte phenotype. Of note, eBD organoids derived from a cystic fibrosis (CF) patient, harboring the same CFTR mutation (dF508-R1162X) as found in the patient, showed normal Ca2+-dependent Cl- channel and MDR-1 transporter activity but no CFTR channel activity. In conclusion, we here show feasibility of expanding eBD organoids with distinct properties when compared to iBD organoids. These eBD organoids may provide an excellent model for studying bile duct diseases and regenerative medicine.

| EGAS00001003792 | EGA

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

Project description:RNA-Sequencing was performed on mechanically dissociated, epithelial-enriched samples, of human extrahepatic biliary tissue from Gallbladder, Common Bile Duct, and Pancreatic Duct tissues. Sequencing was also performed on in vitro cultures of Organoid cell lines at passage 5 that were derived from human Gallbladder, Common Bile Duct, Pancreatic Duct, or Intrahepatic Bile Ducts.

2019-01-20 | E-MTAB-7569 | biostudies-arrayexpress

RNA-seq analysis of hilar and peripheral biliary organoids from a mouse model of Alagille syndrome

Project description:To study molecular differences in wild-type and regenrated bile ducts in a mouse model of Alagille syndrome (Andersson, Chivukula, Hankeova, et al. Gastroenterology, 2018;154(4):1080-1095), we derived intrahepatic cholangiocyte organoids from hilar (pICOs) and peripheral (pICOs) regions of adult livers following a published protocol for organoids derivation and culture (Broutier et al., Nat Protoc. 2016;11:1724–1743). At passage 5, we isolated total RNA and performed bulk RNA-sequencing on 3 biological replicates from each region and genotype.

2023-12-02 | GSE229527 | GEO

Human bile cholangiocyte organoids originate from the extrahepatic bile duct and can repair bile duct scaffolds in vitro

Project description:Cholangiocyte organoids provide a powerful tool for characterizing bile duct epithelium and expanding cholangiocytes for tissue engineering purposes. However, this involves invasively obtained tissue-biopsies via surgery which is not preferential and limits the patient-specific capacities of these cultures. To overcome this, organoid culture were initiated from minimal invasive bile-samples obtained during routine clinical procedures. Characterization revealed that these bile-cholangiocyte organoids originate from the extrahepatic bile duct and are capable to repopulate human extrahepatic bile duct scaffolds. With this, bile duct tissue engineering as well as personalized disease modelling is in sight.

2020-11-19 | GSE156519 | GEO

Prominin-1 promotes restitution of the murine extrahepatic biliary luminal epithelium following cholestatic liver injury

Project description:Restitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury. Utilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands (PBGs) of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly more than ten-fold dilated PBGs following rhesus rotavirus-mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility. We, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.

2022-12-05 | GSE220054 | GEO

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