Mouse liver assembloids model periportal architecture and biliary fibrosis [bulk RNA-seq]
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PROVIDER: PRJNA1148659 | ENA |
REPOSITORIES: ENA
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Project description:Modelling liver disease requires in vitro systems that replicate disease progression1,2. Current tissue-derived organoids fail to reproduce the complex cellular composition and tissue architecture observed in vivo3. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids (HepOrg) with functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Strikingly, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof-of-concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Taken together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage, and how different cell types contribute to cholestatic disease and biliary fibrosis, in an all-in-one model.
2025-04-29 | GSE274973 | GEO
Project description:Modelling liver disease has been hampered by the lack of in vitro systems that represent disease progression. Tissue-derived organoids fail to reproduce the complex cellular composition and the tissue architecture. Here, we describe an organoid model composed of adult hepatocytes, cholangiocytes and liver mesenchymal cells that reconstructs the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids (HepOrg) with functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that recapitulate the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Strikingly, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or from cells after gene knockdown, we show proof-of-concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Summarizing, we demonstrate that liver assembloids represent the first in vitro system suitable to study bile canaliculi formation, bile drainage, and the contributions of the different cell types to cholestatic disease and biliary fibrosis, in an all-in-one model.
2025-04-29 | GSE274971 | GEO
Project description:Mouse liver assembloids model periportal architecture and biliary fibrosis [scRNA-seq]
| PRJNA1148662 | ENA
Project description:Transplantation of pluripotent stem cell (PSC) derived liver organoids have been studied to solve the donor shortage. However, differentiation of unintended cell populations, challenges in generating multi-lineage organoids, and tumorigenicity hinder its uses in clinics. Here, liver assembloids (iHEA) were generated by integrating induced endothelial cells (iEC) and induced hepatic stem cells (iHepSC). iHEA showed enhanced functional maturity iHepSCs derived liver organoids (iHLO) in vitro and had improved therapeutic effects on cholestatic liver fibrosis animals in vivo. Mechanistically, FN1 expressed from iECs led to up-regulation of Itgalph5/beta1 and Hnf4alpha in iHEA and were correlated to decrease of hepatic stellate cells activation genes such as Lox, and Spp1 in the cholestatic liver fibrosis animals. In conclusion, our study demonstrates that directly converted cells can be a promising source for generating transplantable assembloids. This study is designed to generate liver organoids (iHLO) and liver assembloids (iHEA) using induced stem cells generated by direct conversion. Hepatic maturity of iHLO and iHEA were compared by measuring gene expression, albumin/urea secretion and CYP1A2 activity. The experiments were repeated at least three times, and the replicates are indicated in each figure and legend. N values represent the number of animals in the experiment. All animal experimental procedures were approved and conducted under a protocol (UNISTIACUC-20-49) by the Animal Care and Use Committee of Ulsan National Institute of Science and Technology (UNIST, Ulsan, South Korea). The experiments were carried out in accordance with documented standards of the Institutional Review Board of Ulsan National Institute of Science and Technology (UNIST) (UNISTIRB-15–17 C) for human cell experiments.
2022-08-03 | GSE193768 | GEO
Project description:Biliary diseases can cause inflammation, fibrosis, bile duct destruction and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have purified human Biliary Epithelial Cells (hBEC) from discarded human livers. hBECs were tested as a cell therapy in a mouse model of biliary disease where the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures and fibrosis. hBEC are expandable, phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.
2022-03-03 | GSE155498 | GEO
Project description:Throughout the various stages of tooth development, reciprocal epithelial-mesenchymal interactions are the driving force, for instance crucially involved in the differentiation of mature enamel-forming ameloblasts and dentin-producing odontoblasts. Here we established mouse tooth ‘assembloids’, comprised of tooth organoid-derived dental epithelial cells (from mouse molars and incisors) cultured together with molar dental pulp stem cells (DPSCs), to mimic these developmental interactions. Assembloids from both tooth types were grown both in basal- and differentiation-inducing conditions. Single cell transcriptomics analysis was applied to in detail characterize and validate the newly developed mouse tooth assembloid model and evaluate the induced differentiation processes.
2023-04-19 | E-MTAB-12544 | biostudies-arrayexpress
Project description:We established a colon assembloid system comprising epithelium and diverse subtypes of stromal cells. To explore how closely assembloids resemble the native tissue, we performed the transcriptional profiling of stromal cells from assembloids and epithelial cells from assembloids, organoids, and colon tissue at the single-cell level.
2023-05-12 | GSE231716 | GEO
Project description:BACKGROUND: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. METHODS: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. RESULTS: Fourteen of 47 livers displayed prominent features of inflammation (N=9) or fibrosis (N=5), with the remainder showing similar levels of both simultaneously. Differential profiling of gene expression of the 14 livers displayed a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. CONCLUSION: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes. Clinical and laboratory data and liver biopies were obtained from 47 infants at diagnosis of biliary atresia and every 3-6 month intervals until 2 years of age as part of a prospective, observational study of the Biliary Atresia Research Consortium. Liver biopsies underwent histological scoring and those specimens classified as inflammation or fibrosis were used to generate a group-specific gene expression profile. The profile was used to assign a molecular stages of inflammation or fibrosis to the entire cohort. Molecular groups were tested for biological plausibility using immunostaining to quantify hepatic inflammatory cells, and quantitative PCR to reproduce the expression of gene groups and the expression of collagen genes. They were also tested for clinical relevance by testing of association with indicators of liver function, complications of disease, and clinical outcome. This dataset is part of the TransQST collection.
2010-08-31 | E-GEOD-15235 | biostudies-arrayexpress
Project description:CCL24 is a profibrotic, proinflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Mdr2-/- mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24 neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under profibrotic conditions in primary human cholangiocytes and macrophages and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of PSC patients. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in PSC patients via reduced liver inflammation, fibrosis and cholestasis.
2023-04-30 | GSE228596 | GEO
Project description:CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis
| PRJNA950414 | ENA