title: In vitropatterning of pluripotent stem cell-derived intestine recapitulatesin vivohuman development.
abstract: The intestine plays a central role in digestion, nutrient absorption and metabolism, with individual regions of the intestine having distinct functional roles. Many examples of region-specific gene expression in the adult intestine are known, but how intestinal regional identity is established during development is a largely unresolved issue. Here, we have identified several genes that are expressed in a region-specific manner in the developing human intestine. Using human embryonic stem cell-derived intestinal organoids, we demonstrate that the duration of exposure to active FGF and WNT signaling controls regional identity. Short-term exposure to FGF4 and CHIR99021 (a GSK3β inhibitor that stabilizes β-catenin) resulted in organoids with gene expression patterns similar to developing human duodenum, whereas longer exposure resulted in organoids similar to ileum. When region-specific organoids were transplanted into immunocompromised mice, duodenum-like organoids and ileum-like organoids retained their regional identity, demonstrating that regional identity of organoids is stable after initial patterning occurs. This work provides insights into the mechanisms that control regional specification of the developing human intestine and provides new tools for basic and translational research.
authors.affiliation: Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yu-Hwai
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.|Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Nattiv
authors.affiliation: Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Priya H
authors.initials: PH
authors.lastname: Dedhia
authors.affiliation: Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Nagy
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Alana M
authors.initials: AM
authors.lastname: Chin
authors.affiliation: Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94143, USA matthew.thomson@ucsf.edu ophir.klein@ucsf.edu spencejr@umich.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomson
authors.affiliation: Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA matthew.thomson@ucsf.edu ophir.klein@ucsf.edu spencejr@umich.edu.|Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA matthew.thomson@ucsf.edu ophir.klein@ucsf.edu spencejr@umich.edu.|Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jason R
authors.identifier: 0000-0001-7869-3992
authors.initials: JR
authors.lastname: Spence
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D019295:Computational Biology; D047108:Embryonic Development / Q000235:genetics; D005333:Fetus / Q000196:embryology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007422:Intestines / Q000196:embryology*; D051379:Mice; D009940:Organoids / Q000378:metabolism / Q000637:transplantation; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors
keywords: Human; Intestine; Organoid; Patterning; Pluripotent stem cells