title: Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals.
abstract: Adult stem cells are the ultimate source for replenishment of salivary gland (SG) tissue. Self-renewal ability of stem cells is dependent on extrinsic niche signals that have not been unraveled for the SG. The ductal compartment in SG has been identified as the location harboring stem cells. Here, we report that rare SG ductal EpCAM(+) cells express nuclear β-catenin, indicating active Wnt signaling. In cell culture experiments, EpCAM(high) cells respond potently to Wnt signals stimulating self-renewal and long-term expansion of SG organoids, containing all differentiated SG cell types. Conversely, Wnt inhibition ablated long-term organoid cultures. Finally, transplantation of cells pre-treated with Wnt agonists into submandibular glands of irradiated mice successfully and robustly restored saliva secretion and increased the number of functional acini in vivo. Collectively, these results identify Wnt signaling as a key driver of adult SG stem cells, allowing extensive in vitro expansion and enabling restoration of SG function upon transplantation.
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands.
authors.forename: Martti
authors.initials: M
authors.lastname: Maimets
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rocchi
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands.
authors.forename: Reinier
authors.initials: R
authors.lastname: Bron
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pringle
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Kuipers
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
authors.forename: Ben N G
authors.initials: BN
authors.lastname: Giepmans
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
authors.forename: Robert G J
authors.initials: RG
authors.lastname: Vries
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Biology of Aging, Section Stem Cell Biology, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
authors.affiliation: Department of Biology of Aging, Section Stem Cell Biology, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: van Os
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands. Electronic address: r.p.coppes@umcg.nl.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Coppes
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D002478:Cells, Cultured; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D011833:Radiation Injuries, Experimental / Q000628:therapy; D012469:Salivary Glands / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D051176:beta Catenin