Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

Maimets, Martti; Rocchi, Cecilia; Bron, Reinier; Pringle, Sarah; Kuipers, Jeroen; Giepmans, Ben N. G.; Vries, Robert G. J.; Clevers, Hans; Haan, Gerald de; Os, Ronald van; Coppes, Robert P.

doi:10.1016/j.stemcr.2015.11.009

Cited by 200 publications

(247 citation statements)

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“…In a follow-up study, robust Wnt pathway activation through the addition of Wnt3A and R-spondin allowed long-term expansion of the organoids, containing all differentiated salivary gland cell types. Transplantation of these cells into submandibular glands of irradiated mice robustly restored saliva secretion and increased the number of functional acini in vivo (Maimets et al, 2016). Since post-radiation hyposalivation often leads to irreversible and untreatable xerostomia, this condition may present an early opportunity for the development of organoid technology-based cell therapy.…”

Section: Salivary Glandmentioning

confidence: 99%

Modeling Development and Disease with Organoids

Clevers

2016

Cell

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Recent advances in 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina. Organoid technology can therefore be used to model human organ development and various human pathologies 'in a dish." Additionally, patient-derived organoids hold promise to predict drug response in a personalized fashion. Organoids open up new avenues for regenerative medicine and, in combination with editing technology, for gene therapy. The many potential applications of this technology are only beginning to be explored.

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Section: Salivary Glandmentioning

confidence: 99%

Modeling Development and Disease with Organoids

Clevers

2016

Cell

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“…Loss of VEGFR2/CD31 + endothelial cell function would then be expected to increase canonical Wnt signaling to the epithelium, prevent proacinar differentiation, downregulate Kit expression and accelerate ductal formation. Wnt signaling is regulated by balancing activation of Wnt receptors by ligands at many levels, and several reports indicate that the Wnt family has complex roles in SMG development (Haara et al, 2011;Musselmann et al, 2011;Patel et al, 2011;Knosp et al, 2015;Maimets et al, 2016;Matsumoto et al, 2016). Thus, VEGFR2/CD31 + endothelial cells could act in many ways to modulate mesenchymal Wnt signaling to the epithelium, and might confer this regulation in a spatially restricted manner during branching morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell regulation of salivary gland epithelial patterning

et al. 2017

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Perfusion-independent regulation of epithelial pattern formation by the vasculature during organ development and regeneration is of considerable interest for application in restoring organ function. During murine submandibular salivary gland development, the vasculature co-develops with the epithelium during branching morphogenesis; however, it is not known whether the vasculature has instructive effects on the epithelium. Using pharmacological inhibitors and siRNA knockdown in embryonic organ explants, we determined that VEGFR2-dependent signaling is required for salivary gland epithelial patterning. To test directly for a requirement for endothelial cells in instructive epithelial patterning, we developed a novel ex vivo cell fractionation/reconstitution assay. Immunodepletion of CD31 + endothelial cells in this assay confirmed a requirement for endothelial cells in epithelial patterning of the gland. Depletion of endothelial cells or inhibition of VEGFR2 signaling in organ explants caused an aberrant increase in cells expressing the ductal proteins K19 and K7, with a reduction in Kit + progenitor cells in the endbuds of reconstituted glands. Addition of exogenous endothelial cells to reconstituted glands restored epithelial patterning, as did supplementation with the endothelial cell-regulated mesenchymal factors IGFBP2 and IGFBP3. Our results demonstrate that endothelial cells promote expansion of Kit + progenitor cells and suppress premature ductal differentiation in early developing embryonic submandibular salivary gland buds.

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“…These include mouse and human liver (Huch et al, 2013a, pancreas (Boj et al, 2015;Huch et al, 2013b), stomach (Barker et al, 2010;Bartfeld et al, 2015), fallopian tube (Kessler et al, 2015), prostate (Chua et al, 2014;Karthaus et al, 2014), taste buds (Ren et al, 2014) and salivary gland (Maimets et al, 2016). Although not discussed in detail here, organoids can also be derived from pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells.…”

Section: Introductionmentioning

confidence: 99%

Translational applications of adult stem cell-derived organoids

2017

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Adult stem cells from a variety of organs can be expanded longterm in vitro as three-dimensional organotypic structures termed organoids. These adult stem cell-derived organoids retain their organ identity and remain genetically stable over long periods of time. The ability to grow organoids from patient-derived healthy and diseased tissue allows for the study of organ development, tissue homeostasis and disease. In this Review, we discuss the generation of adult stem cell-derived organoid cultures and their applications in in vitro disease modeling, personalized cancer therapy and regenerative medicine.

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Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

Cited by 200 publications

References 50 publications

Modeling Development and Disease with Organoids

Modeling Development and Disease with Organoids

Endothelial cell regulation of salivary gland epithelial patterning

Translational applications of adult stem cell-derived organoids

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