Wnt/β-Catenin Signaling Regulates Postnatal Development and Regeneration of the Salivary Gland
Wnt/β-Catenin Signaling Regulates Postnatal Development and Regeneration of the Salivary Gland
复制标题
DOI：
10.1089/scd.2009.0499
复制
发表时间：
2010-11-01
影响因子：
4
通讯作者：
Liu, Fei
中科院分区：
文献类型：
--
作者：
Hai, Bo;Yang, Zhenhua;Liu, Fei
唾液腺再生治疗是治疗头颈部恶性肿瘤放疗后不可逆性少涎的有效方法。然而，很少有人知道的干/祖细胞的活性和再生过程中的SG的分子调节。Wnt/β-连环蛋白信号调节许多成体干细胞群的功能，但其在SG发育和再生中的作用尚不清楚。使用BAT-gal Wnt报告基因转基因小鼠，我们证明了在新生小鼠的下颌下腺（SMG）中，Wnt/β-连环蛋白信号传导在闰管基底层的少数细胞中是活跃的，闰管是唾液腺干/祖细胞（SGPC）的假定位置。Wnt活性随着小鼠年龄的增长而降低，但在成年SMG结扎后的再生过程中，SG导管中的Wnt活性显著增强。Hedgehog（Hh）通路在导管结扎后也被激活。在年轻的角蛋白5-rtTA/tetO-Dkk 1小鼠中抑制上皮β-连环蛋白信号传导损害SMG的出生后发育，特别是影响颗粒曲小管的成熟。相反，在成年角蛋白5-rtTA/tetO-Cre/Ctnnb 1（（Ex 3）ft）小鼠中，上皮β-连环蛋白信号传导的强制激活促进导管细胞的增殖、SGPC区室的扩张和Hh信号传导的异位激活。总之，这些结果表明，Wnt/β-catenin信号调节的活性，在出生后的发展和再生的Hh通路上游的SGPC，并建议的潜力，调节Wnt/β-catenin和/或Hh通路的功能恢复的SG照射后。
Regenerative therapy of the salivary gland (SG) is a promising therapeutic approach for irreversible hyposalivation in patients with head and neck cancer treated by radiotherapy. However, little is known about the molecular regulators of stem/progenitor cell activity and regenerative processes in the SG. Wnt/beta-catenin signaling regulates the function of many adult stem cell populations, but its role in SG development and regeneration is unknown. Using BAT-gal Wnt reporter transgenic mice, we demonstrate that in the submandibular glands (SMGs) of newborn mice Wnt/beta-catenin signaling is active in a few cells at the basal layer of intercalated ducts, the putative location of salivary gland stem/progenitor cells (SGPCs). Wnt activity decreases as mice age, but is markedly enhanced in SG ducts during regeneration of adult SMG after ligation of the main secretory duct. The Hedgehog (Hh) pathway is also activated after duct ligation. Inhibition of epithelial beta-catenin signaling in young Keratin5-rtTA/tetO-Dkk1 mice impairs the postnatal development of SMG, particularly affecting maturation of granular convoluted tubules. Conversely, forced activation of epithelial beta-catenin signaling in adult Keratin5-rtTA/tetO-Cre/Ctnnb1((Ex3)ft) mice promotes proliferation of ductal cells, expansion of the SGPC compartment, and ectopic activation of Hh signaling. Taken together, these results indicate that Wnt/beta-catenin signaling regulates the activity of SGPCs during postnatal development and regeneration upstream of the Hh pathway, and suggest the potential of modulating Wnt/beta-catenin and/or Hh pathways for functional restoration of SGs after irradiation.