Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Oral Immunobiology Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
J Dent Res. 2019 Oct;98(11):1186-1194. doi: 10.1177/0022034519864592. Epub 2019 Jul 22.
Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren's syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.
维持唾液腺功能对于口腔健康至关重要。头颈部癌症或干燥综合征等自身免疫性疾病的治疗性放疗会导致唾液流失，这是一种常见的副作用。目前尚无治愈方法，目前提出的用于功能再生的策略包括基因治疗以重新设计存活的唾液腺组织、基于细胞的移植治疗、使用生物工程化腺体以及开发药物/生物制剂以刺激体内再生或增加分泌。了解成年腺体发育和稳态所需的遗传和细胞机制对于这些治疗方法的成功至关重要。遗传谱系追踪的最新进展为了解小鼠唾液腺发育过程中的上皮谱系关系提供了线索。在早期胎儿腺体发育过程中，表达角蛋白 14 (K14)、Sox2、Sox9、Sox10 和 Trp63 的上皮细胞产生所有成年上皮细胞，但随着发育的进行，谱系限制发生，导致出生后腺体中的肌上皮细胞、导管细胞和腺泡细胞分离。已经确定了几个调节上皮发育和谱系限制的龛位信号。成纤维细胞生长因子信号对于腺体发育至关重要，其他影响上皮模式形成和成熟的重要因素包括 Wnt、Hedgehog、视黄酸和 Hippo 信号通路。此外，局部微环境中的其他细胞类型，如内皮细胞和神经元细胞，也可以影响上皮发育。新出现的证据还表明，特定的上皮细胞将根据唾液腺损伤的类型、严重程度和由此产生的损伤微环境对不同类型的损伤做出反应。了解再生是如何发生的，哪些细胞类型受到影响，以及哪些信号因子驱动细胞谱系决定，为操纵细胞命运和改善再生提供了具体目标。综上所述，这些关于细胞谱系和驱动细胞命运变化的信号因子的最新进展为开发新的再生治疗方法提供了指导。
