Toan Nguyen Khanh, Kim Soo-A, Ahn Sang-Gun
Department of Pathology, School of Dentistry, Chosun University, Gwangju, Republic of Korea.
Department of Biochemistry, School of Oriental Medicine, Dongguk University, Gyeongju, Republic of Korea.
Aging Cell. 2024 Dec;23(12):e14329. doi: 10.1111/acel.14329. Epub 2024 Sep 6.
Salivary gland branching morphogenesis is regulated by the functional integration of neuronal signaling, but the underlying mechanisms are not fully understood in aging accelerated klotho-deficient (Kl) mice. Here, we investigated whether the neuropeptides substance P (SP) and neuropeptide Y (NPY) affect the branching morphogenesis of embryonic salivary glands in aging Kl mice. In the salivary glands of embryonic Kl mice, morphological analysis and immunostaining revealed that epithelial bud formation, neuronal cell proliferation/differentiation, and the expression of the salivary gland functional marker ZO-1 were decreased in embryonic ductal cells. Incubation with SP/NPY at E12-E13d promoted branching morphogenesis, parasympathetic innervation, and epithelial proliferation in salivary glands of embryonic Kl mice. The ERK inhibitor U0126 specifically inhibited neuronal substance-induced epithelial bud formation in the embryonic salivary gland. RNA-seq profiling analysis revealed that the expression of fibroblast growth factors/fibroblast growth factors (FGFs/FGFRs) and their receptors was significantly regulated by SP/NPY treatment in the embryonic salivary gland (E15). The FGFR inhibitor BGJ389 inhibited new branching formation induced by SP and NPY treatment and ERK1/2 expression. These results showed that aging may affect virtually the development of salivary gland by neuronal dysfunction. The neuropeptides SP/NPY induced embryonic salivary gland development through FGF/FGFR/ERK1/2-mediated signaling.
唾液腺分支形态发生受神经信号功能整合的调节，但在衰老加速的klotho缺陷（Kl）小鼠中，其潜在机制尚未完全明确。在此，我们研究了神经肽P物质（SP）和神经肽Y（NPY）是否影响衰老Kl小鼠胚胎唾液腺的分支形态发生。在胚胎Kl小鼠的唾液腺中，形态学分析和免疫染色显示，胚胎导管细胞中的上皮芽形成、神经细胞增殖/分化以及唾液腺功能标志物ZO-1的表达均降低。在胚胎第12 - 13天用SP/NPY孵育可促进胚胎Kl小鼠唾液腺的分支形态发生、副交感神经支配和上皮增殖。ERK抑制剂U0126特异性抑制胚胎唾液腺中神经物质诱导的上皮芽形成。RNA测序分析显示，在胚胎唾液腺（胚胎第15天）中，成纤维细胞生长因子/成纤维细胞生长因子（FGFs/FGFRs）及其受体的表达受SP/NPY处理的显著调控。FGFR抑制剂BGJ389抑制了SP和NPY处理诱导的新分支形成以及ERK1/2表达。这些结果表明，衰老可能通过神经功能障碍实际上影响唾液腺的发育。神经肽SP/NPY通过FGF/FGFR/ERK1/2介导的信号通路诱导胚胎唾液腺发育。
