title: Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis.
abstract: Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5(+) stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality.
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Meritxell
authors.identifier: 0000000215455265
authors.initials: M
authors.lastname: Huch
authors.forename: Paola
authors.initials: P
authors.lastname: Bonfanti
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Boj
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Cindy J M
authors.initials: CJ
authors.lastname: Loomans
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.forename: Mozhdeh
authors.initials: M
authors.lastname: Sojoodi
authors.forename: Vivian S W
authors.initials: VS
authors.lastname: Li
authors.forename: Jurian
authors.initials: J
authors.lastname: Schuijers
authors.forename: Ana
authors.initials: A
authors.lastname: Gracanin
authors.forename: Femke
authors.initials: F
authors.lastname: Ringnalda
authors.forename: Harry
authors.initials: H
authors.lastname: Begthel
authors.forename: Karien
authors.initials: K
authors.lastname: Hamer
authors.forename: Joyce
authors.initials: J
authors.lastname: Mulder
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Eelco
authors.initials: E
authors.lastname: de Koning
authors.forename: Robert G J
authors.initials: RG
authors.lastname: Vries
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C493597:Lgr5 protein, mouse; C518903:RSPO1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins
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