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.
Department of Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Stem Cell Reports. 2016 Jan 12;6(1):150-62. doi: 10.1016/j.stemcr.2015.11.009. Epub 2015 Dec 24.
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.
成体干细胞是唾液腺 (SG) 组织再生的最终来源。干细胞的自我更新能力依赖于尚未阐明的外源性生态位信号。SG 的导管隔室已被确定为含有干细胞的位置。在这里，我们报告说，罕见的 SG 导管 EpCAM(+)细胞表达核 β-连环蛋白，表明存在活跃的 Wnt 信号。在细胞培养实验中，EpCAM(高)细胞对 Wnt 信号有强烈反应，刺激 SG 类器官的自我更新和长期扩增，其中包含所有分化的 SG 细胞类型。相反，Wnt 抑制消除了长期类器官培养。最后，用 Wnt 激动剂预处理的细胞移植到辐射小鼠的颌下腺中，成功且强烈地恢复了唾液分泌，并增加了体内功能性腺泡的数量。总的来说，这些结果表明 Wnt 信号是成体 SG 干细胞的关键驱动因素，允许其在体外进行广泛扩增，并在移植后恢复 SG 功能。
