title: Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model.
abstract: Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion. Inflammation-associated liver dysfunction was mimicked by stimulation with various agonists of toll-like receptors. TLR-stimulation induced the release of pro- and anti-inflammatory cytokines and diminished expression of endothelial VE-cadherin, hepatic MRP-2 transporter and apolipoprotein B (ApoB), resulting in an inflammation-related endothelial barrier disruption and hepatocellular dysfunction in the liver organoid. However, interaction of the liver organoid with human monocytes attenuated inflammation-related cell responses and restored MRP-2 transporter activity, ApoB expression and albumin/urea production. The cellular events observed in the liver organoid closely resembled pathophysiological responses in the well-established sepsis model of peritoneal contamination and infection (PCI) in mice and clinical observations in human sepsis. We therefore conclude that this human liver organoid model is a valuable tool to investigate sepsis-related liver dysfunction and subsequent immune cell-related tissue repair/remodeling processes.
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Gröger
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Rennert
authors.affiliation: Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena 07747 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Giszas
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weiß
authors.affiliation: Institute of Forensic Medicine, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dinger
authors.affiliation: Molecular Hemostaseology, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Funke
authors.affiliation: Institute of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, 07747 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehntopf
authors.affiliation: Institute of Forensic Medicine, Jena University Hospital, 07743 Jena, Germany.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Peters
authors.affiliation: Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Lupp
authors.affiliation: Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena 07747 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena 07747 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743 Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747 Jena, Germany.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mosig
mesh_terms: D000418:Albumins / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001055:Apolipoproteins B / Q000235:genetics / Q000276:immunology; D015820:Cadherins / Q000235:genetics / Q000276:immunology; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D056656:Lab-On-A-Chip Devices; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000276:immunology; D009940:Organoids / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D000099152:Cadherin 5
chemical_list: D000418:Albumins; D015703:Antigens, CD; D001055:Apolipoproteins B; D015820:Cadherins; D016207:Cytokines; D008070:Lipopolysaccharides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051193:Toll-Like Receptors; D000099152:Cadherin 5; C000715087:ABCC2 protein, human