Role for Notch signaling in salivary acinar cell growth and differentiation.

The Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. The Notch signaling is essential for Drosophila salivary gland development but its role in mammalian salivary gland remains unclear. The human salivary epithelial cell line, HSG, was studied to determine the role of Notch signaling in salivary epithelial cell differentiation. HSG expressed Notch 1 to 4, and the Notch ligands Jagged 1 and 2 and Delta 1. Treatment of HSG cells with inhibitors of γ-secretase, which is required for Notch cleavage and activation, blocked vimentin expression, an indicator of HSG differentiation. HSG differentiation was also associated with Notch downsteam signal Hes-1 expression, and Hes-1 expression was inhibited by γ-secretase inhibitors. siRNA corresponding to Notch 1 to 4 was used to show that silencing of all four Notch receptors was required to inhibit HSG differentiation. Normal human submandibular gland expressed Notch 1 to 4, Jagged 1 and 2, and Delta 1, with nuclear localization indicating Notch signaling in vivo. Hes-1 was also expressed in the human tissue, with staining predominantly in the ductal cells. In salivary tissue from rats undergoing and recovering from ductal obstruction, we found that Notch receptors and ligands were expressed in the nucleus of the regenerating epithelial cells. Taken together, these data suggest that Notch signaling is critical for normal salivary gland cell growth and differentiation.

Notch通路对于多种组织中干细胞/祖细胞的维持、生长和分化至关重要。Notch信号对于果蝇唾液腺的发育必不可少，但其在哺乳动物唾液腺中的作用仍不明确。对人唾液腺上皮细胞系HSG进行了研究，以确定Notch信号在唾液腺上皮细胞分化中的作用。HSG表达Notch 1 - 4，以及Notch配体Jagged 1、Jagged 2和Delta 1。用γ - 分泌酶抑制剂处理HSG细胞（γ - 分泌酶是Notch切割和激活所必需的），可阻断波形蛋白的表达，波形蛋白是HSG分化的一个指标。HSG分化还与Notch下游信号Hes - 1的表达相关，并且Hes - 1的表达被γ - 分泌酶抑制剂抑制。使用对应于Notch 1 - 4的小干扰RNA（siRNA）表明，抑制HSG分化需要沉默所有四种Notch受体。正常人下颌下腺表达Notch 1 - 4、Jagged 1和Jagged 2以及Delta 1，核定位表明体内存在Notch信号。Hes - 1也在人体组织中表达，主要在导管细胞中染色。在经历导管阻塞以及从导管阻塞中恢复的大鼠唾液组织中，我们发现Notch受体和配体在再生上皮细胞的细胞核中表达。综上所述，这些数据表明Notch信号对于正常唾液腺细胞的生长和分化至关重要。