Cell-matrix interactions control biliary organoid polarity, architecture, and differentiation.

Autor:	Fiorotto R; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA., Mariotti V; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA., Taleb SA; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA., Zehra SA; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA., Nguyen M; Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA., Amenduni M; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA., Strazzabosco M; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
Jazyk:	angličtina
Zdroj:	Hepatology communications [Hepatol Commun] 2023 Mar 24; Vol. 7 (4). Date of Electronic Publication: 2023 Mar 24 (Print Publication: 2023).
DOI:	10.1097/HC9.0000000000000094
Abstrakt:	Background and Aims: Cholangiopathies are an important cause of morbidity and mortality. Their pathogenesis and treatment remain unclear in part because of the lack of disease models relevant to humans. Three-dimensional biliary organoids hold great promise; however, the inaccessibility of their apical pole and the presence of extracellular matrix (ECM) limits their application. We hypothesized that signals coming from the extracellular matrix regulate organoids' 3-dimensional architecture and could be manipulated to generate novel organotypic culture systems. Approach and Results: Biliary organoids were generated from human livers and grown embedded into Culturex Basement Membrane Extract as spheroids around an internal lumen (EMB). When removed from the EMC, biliary organoids revert their polarity and expose the apical membrane on the outside (AOOs). Functional, immunohistochemical, and transmission electron microscope studies, along with bulk and single-cell transcriptomic, demonstrate that AOOs are less heterogeneous and show increased biliary differentiation and decreased expression of stem cell features. AOOs transport bile acids and have competent tight junctions. When cocultured with liver pathogenic bacteria (Enterococcus spp.), AOOs secrete a range of proinflammatory chemokines (ie, MCP1, IL8, CCL20, and IP-10). Transcriptomic analysis and treatment with a beta-1-integrin blocking antibody identified beta-1-integrin signaling as a sensor of the cell-extracellular matrix interaction and a determinant of organoid polarity. Conclusions: This novel organoid model can be used to study bile transport, interactions with pathobionts, epithelial permeability, cross talk with other liver and immune cell types, and the effect of matrix changes on the biliary epithelium and obtain key insights into the pathobiology of cholangiopathies. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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