title: R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders.
abstract: Pioneering studies within the last few years have allowed the in vitro expansion of tissue-specific adult stem cells from a variety of endoderm-derived organs, including the stomach, small intestine, and colon. Expansion of these cells requires activation of the receptor Lgr5 by its ligand R-spondin 1 and is likely facilitated by the fact that in healthy adults the stem cells in these organs are highly proliferative. In many other adult organs, such as the liver, proliferating cells are normally not abundant in adulthood. However, upon injury, the liver has a strong regenerative potential that is accompanied by the emergence of Lgr5-positive stem cells; these cells can be isolated and expanded in vitro as organoids. In an effort to isolate stem cells from non-regenerating mouse livers, we discovered that healthy gallbladders are a rich source of stem/progenitor cells that can be propagated in culture as organoids for more than a year. Growth of these organoids was stimulated by R-spondin 1 and noggin, whereas in the absence of these growth factors, the organoids differentiated partially toward the hepatocyte fate. When transplanted under the liver capsule, gallbladder-derived organoids maintained their architecture for 2 weeks. Furthermore, single cells prepared from dissociated organoids and injected into the mesenteric vein populated the liver parenchyma of carbon tetrachloride-treated mice. Human gallbladders were also a source of organoid-forming stem cells. Thus, under specific growth conditions, stem cells can be isolated from healthy gallbladders, expanded almost indefinitely in vitro, and induced to differentiate toward the hepatocyte lineage.
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva, Switzerland National Centre of Competence in Research "Frontiers in Genetics", Geneva, Switzerland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lugli
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Kamileri
authors.affiliation: Department of Clinical Research, Clinic of Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.affiliation: Department of Clinical Research, Clinic of Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Malinka
authors.affiliation: Biomedical Sciences Research Center Alexander Fleming, Vari, Greece.
authors.forename: Michalis E
authors.initials: ME
authors.lastname: Sarris
authors.affiliation: Biomedical Sciences Research Center Alexander Fleming, Vari, Greece.
authors.forename: Iannis
authors.initials: I
authors.lastname: Talianidis
authors.affiliation: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schaad
authors.affiliation: Department of Clinical Research, Clinic of Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Candinas
authors.affiliation: Department of Clinical Research, Clinic of Visceral Surgery and Medicine, University of Bern, Bern, Switzerland deborah.stroka@dkf.unibe.ch thanos.halazonetis@unige.ch.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stroka
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva, Switzerland deborah.stroka@dkf.unibe.ch thanos.halazonetis@unige.ch.
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D000818:Animals; D015415:Biomarkers; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005704:Gallbladder / Q000166:cytology*; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009940:Organoids; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D059467:Transcriptome; D000099176:Noggin Protein
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D019699:Thrombospondins; D000099176:Noggin Protein; C518903:RSPO1 protein, mouse
keywords: R‐spondin 1; gallbladder; noggin; organoids; stem cells