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

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

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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.

Original languageEnglish
Pages (from-to)150-162
Number of pages13
JournalStem Cell Reports
Volume6
Issue number1
Early online date24 Dec 2015
DOIs
Publication statusPublished - 12 Jan 2016

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    Maimets, M., Rocchi, C., Bron, R., Pringle, S., Kuipers, J., Giepmans, B. N. G., Vries, R. G. J., Clevers, H., de Haan, G., van Os, R., & Coppes, R. P. (2016). Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals. Stem Cell Reports, 6(1), 150-162. https://doi.org/10.1016/j.stemcr.2015.11.009