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

TY - JOUR

T1 - Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

AU - Maimets, Martti

AU - Rocchi, Cecilia

AU - Bron, Reinier

AU - Pringle, Sarah

AU - Kuipers, Jeroen

AU - Giepmans, Ben N G

AU - Vries, Robert G J

AU - Clevers, Hans

AU - de Haan, Gerald

AU - van Os, Ronald

AU - Coppes, Robert P

N1 - Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2016/1/12

Y1 - 2016/1/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.stemcr.2015.11.009

DO - 10.1016/j.stemcr.2015.11.009

M3 - Article

C2 - 26724906

SN - 2213-6711

VL - 6

SP - 150

EP - 162

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 1

ER -