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Mouse liver assembloids model periportal architecture and biliary fibrosis [scRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE274973 | GEO | 2025/04/29

REPOSITORIES: GEO

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Mouse liver assembloids model periportal architecture and biliary fibrosis [bulk RNA-seq]

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.

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Mouse liver assembloids model periportal architecture and biliary fibrosis [scRNA-seq]

Project description:Mouse liver assembloids model periportal architecture and biliary fibrosis [scRNA-seq]

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