title: Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor biology.
abstract: Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets because they are activated by lipophilic ligands that easily pass cell membranes. Immortalized cell lines recapitulate NR biology poorly and generating primary cultures is laborious and requires a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology. Uncertainty due to technical limitations early in drug development is often the cause of preclinical drugs not reaching the clinic. Here, we studied whether organoids, mini-organs derived from the respective mouse tissue's stem cells, can serve as a novel model system to study NR biology and targetability. We characterized mRNA expression profiles of the NR superfamily in mouse liver, ileum, and colon organoids. Tissue-specific expression patterns were largely maintained in the organoids, indicating their suitability for NR research. Metabolic NRs Fxrα, Lxrα, Lxrβ, Pparα, and Pparγ induced expression of and binding to endogenous target genes. Transcriptome analyses of wildtype colon organoids stimulated with Rosiglitazone showed that lipid metabolism was the highest significant changed function, greatly mimicking the PPARs and Rosiglitazone function in vivo. Finally, using organoids we identify Trpm6, Slc26a3, Ang1, and Rnase4, as novel Fxr target genes. Our results demonstrate that organoids represent a framework to study NR biology that can be further expanded to human organoids to improve preclinical testing of novel drugs that target this pharmacologically important class of ligand activated transcription factors.
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ingrid T G W
authors.initials: IT
authors.lastname: Bijsmans
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Milona
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Noortje
authors.initials: N
authors.lastname: Ijssennagger
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen C L
authors.initials: EC
authors.lastname: Willemsen
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: José M
authors.initials: JM
authors.lastname: Ramos Pittol
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.affiliation: Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Katja
authors.initials: K
authors.lastname: Lange
authors.affiliation: Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Guido J E J
authors.initials: GJ
authors.lastname: Hooiveld
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: S.W.C.vanMil@umcutrecht.nl.
authors.forename: Saskia W C
authors.initials: SW
authors.lastname: van Mil
mesh_terms: D000818:Animals; D003106:Colon / Q000166:cytology* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D007082:Ileum / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009924:Organ Culture Techniques / Q000379:methods; D009940:Organoids / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear
keywords: Fxr; Ligands; Lxr; Nuclear receptors; Organoids; Ppar