Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179601 | GEO | 2022/05/04
REPOSITORIES: GEO
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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 | GSE179599 | GEO
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
Project description:Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases.
| PRJNA744244 | ENA
Project description:Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases. RNA-Seq
| PRJNA744255 | ENA
Project description:Human branching cholangiocyte organoids recapitulate embryogenic bile duct development and provide an unique model to study biliary diseases. scRNA-Seq
| PRJNA744254 | ENA
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
Project description:There is no effective treatment for autoimmune biliary diseases. Therefore, understanding their immunopathology is crucial. The biliary epithelial cells (BEC), expressing TLR-4, are constantly exposed to gut microbes and bacterial wall LPS, and in settings of inflammation, the immune infiltrate is dense within the peribiliary region of human liver. By dual immunohistochemistry, we affirm human intrahepatic T cell infiltrate includes CCR6+CD4+ and AhR+CD4+ T cells with potential for plasticity to Th17 phenotype. Mechanistically, we demonstrate that Th1 and Th17 inflammatory cytokines and LPS enhance human primary BEC release of the CCR6 ligand CCL20 and BEC secretion of Th17-polarizing cytokines IL-6 and IL-1?. Cell culture assays with human BEC secretome showed that secretome polarizes CD4 T cells toward a Th17 phenotype and supports the survival of Th17 cells. BEC secretome did not promote Th1 cell generation. Additionally, we give evidence for a mutually beneficial feedback of the type 17 cell infiltrate on BEC, showing that treatment with type 17 cytokines increases BEC proliferation, as monitored by Ki67 and activation of JAK2-STAT3 signaling. This study identifies human BEC as active players in determining the nature of the intrahepatic immune microenvironment. In settings of inflammation and/or infection, biliary epithelium establishes a prominent peribiliary type 17 infiltrate via recruitment and retention and enhances polarization of intrahepatic CD4 cells toward Th17 cells via type 17 cytokines, and, reciprocally, Th17 cells promote BEC proliferation for biliary regeneration. Altogether, we provide new insight into cross-talk between Th17 lymphocytes and human primary biliary epithelium in biliary regenerative pathologies.
| S-EPMC6697739 | biostudies-literature
Project description:In bile duct-ligated (BDL) rats, cholangiocyte proliferation is regulated by neuroendocrine factors such as ?-calcitonin gene-related peptide (?-CGRP). There is no evidence that the sensory neuropeptide substance P (SP) regulates cholangiocyte hyperplasia. Wild-type (WT, (+/+)) and NK-1 receptor (NK-1R) knockout (NK-1R(-/-)) mice underwent sham or BDL for 1 wk. Then we evaluated 1) NK-1R expression, transaminases, and bilirubin serum levels; 2) necrosis, hepatocyte apoptosis and steatosis, and the number of cholangiocytes positive by CK-19 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling in liver sections; 3) mRNA expression for collagen 1? and ?-smooth muscle (?-SMA) actin in total liver samples; and 4) PCNA expression and PKA phosphorylation in cholangiocytes. In cholangiocyte lines, we determined the effects of SP on cAMP and D-myo-inositol 1,4,5-trisphosphate levels, proliferation, and PKA phosphorylation. Cholangiocytes express NK-1R with expression being upregulated following BDL. In normal NK-1R(-/-) mice, there was higher hepatocyte apoptosis and scattered hepatocyte steatosis compared with controls. In NK-1R (-)/(-) BDL mice, there was a decrease in serum transaminases and bilirubin levels and the number of CK-19-positive cholangiocytes and enhanced biliary apoptosis compared with controls. In total liver samples, the expression of collagen 1? and ?-SMA increased in BDL compared with normal mice and decreased in BDL NK-1R(-/-) compared with BDL mice. In cholangiocytes from BDL NK-1R (-)/(-) mice there was decreased PCNA expression and PKA phosphorylation. In vitro, SP increased cAMP levels, proliferation, and PKA phosphorylation of cholangiocytes. Targeting of NK-1R may be important in the inhibition of biliary hyperplasia in cholangiopathies.
| S-EPMC3154601 | biostudies-literature
Project description:Background and aimsThe etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes, and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies. The aim of this study was to discover autoantibodies in BA that correlated with outcomes.Approach and resultsAn autoantigen microarray encompassing approximately 9,500 autoantigens was used to screen for serum immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in patients with BA or other liver disease controls. Validation of candidate autoantibodies by enzyme-linked immunosorbent assay on a second cohort of subjects (6-12 months following Kasai portoenterostomy) and correlations of autoantibodies with outcomes were performed (serum bilirubin levels and need for liver transplant in first 2 years of life). Mean anti-chitinase 3-like 1 (CHI3L1), anti-delta-like ligand (DLL-4), and antisurfactant protein D (SFTPD) IgM autoantibodies in BA were significantly higher compared with controls, and IgM autoantibody levels positively correlated with worse outcomes. Immunofluorescence revealed cholangiocyte-predominant expression of CHI3L1, DLL-4, and SFTPD. The humoral autoantibody response was associated with C3d complement activation and T-cell autoimmunity, based on detection of cholangiocyte-predominant C3d co-staining and peripheral blood autoreactive T cells specific to CHI3L1, DLL-4 and SFTPD, respectively.ConclusionsBA is associated with cholangiocyte-predominant IgM autoantibodies in the first year after Kasai portoenterostomy. Anti-CHI3L1, anti-DLL-4, and anti-SFTPD IgM autoantibody correlations with worse outcomes and the detection of C3d on cholangioctyes and antigen-specific autoreactive T cells suggest that autoimmunity plays a role in the ongoing bile duct injury and progression of disease.
| S-EPMC7867668 | biostudies-literature
Project description:In several clinical situations, including resection of malignant or benign biliary lesions, reconstruction of the biliary system using the Roux-en-Y jejunum limb has been adopted as the standard procedure. The basic technique and the procedural knowledge essential for most gastroenterological surgeons are described in this article, along with a video supplement. Low complication rates involving anastomotic insufficiency or stricture can be achieved by using proper surgical techniques, even following small bile duct reconstruction. Using the ropeway method to stabilize the bile duct and jejunal limb allows precise mucosa-to-mucosa anastomosis with interrupted sutures of the posterior row of the anastomosis. Placement of a transanastomotic stent tube is the second step. The final step involves suturing the anterior row of the anastomosis. In contrast to the lower extrahepatic bile duct, the wall of the hilar or intrahepatic bile duct can be recognized within the fibrous connective tissue in the Glissonean pedicle. The portal side of the duct should be selected for the posterior wall during anastomosis owing to its thickness. Meticulous inspection to avoid overlooking small bile ducts could decrease the chance of postoperative intractable bile leakage. In reconstruction of small or fragile branches, a transanastomotic stent tube could work as an anchor for the anastomosis.
| S-EPMC3311849 | biostudies-literature