Anatomy, biogenesis and regeneration of salivary glands

Abstract

An overview of the anatomy and biogenesis of salivary glands is important in order to understand the physiology, functions and disorders associated with saliva. A major disorder of salivary glands is salivary hypofunction and resulting xerostomia, or dry mouth, which affects hundreds of thousands of patients each year who suffer from salivary gland diseases or undergo head and neck cancer treatment. There is currently no curative therapy for these patients. To improve these patients' quality of life, new therapies are being developed based on findings in salivary gland cell and developmental biology. Here we discuss the anatomy and biogenesis of the major human salivary glands and the rodent submandibular gland, which has been used extensively as a research model. We also include a review of recent research on the identification and function of stem cells in salivary glands, and the emerging field of research suggesting that nerves play an instructive role during development and may be essential for adult gland repair and regeneration. Understanding the molecular mechanisms involved in gland biogenesis provides a template for regenerating, repairing or reengineering diseased or damaged adult human salivary glands. We provide an overview of 3 general approaches currently being developed to regenerate damaged salivary tissue, including gene therapy, stem cell-based therapy and tissue engineering. In the future, it may be that a combination of all three will be used to repair, regenerate and reengineer functional salivary glands in patients to increase the secretion of their saliva, the focus of this monograph.

Figure 1

Overview of salivary gland anatomy. The three major salivary glands are the parotid gland (PG), submandibular gland (SMG), and sublingual gland (SLG). Stensen’s and Wharton’s ducts are the main excretory ducts of the PG and SMG, respectively. Blood supply is mainly provided to the PG by the transverse facial artery and to the SMG by the facial artery. Parasympathetic innervation arises from post-ganglionic nerves from the otic and submandibular ganglia. The otic ganglion is associated closely with the mandibular division of the trigeminal nerve (CN V-III) and the submandibular ganglion is next to the lingual nerve. Sympathetic post-ganglionic nerves (not shown) arise from the superior cervical ganglion and innervate the glands along blood vessels.

Figure 2

The human SMG contains small ganglia within the gland stroma. Three synaptophysin positive nerve cell bodies are arranged in a small ganglion (G) near acini (A), a striated duct (SD) and a blood vessel (V). Figure from Fig.3 in reference [9].

Figure 3

There is close association of the epithelium, nerves, and blood vessels during submandibular gland biogenesis. The projection of confocal sections show immunostaining of the epithelium (blue), parasympathetic nerves (green), and blood vessels (red) of an E13 mouse SMG. The parasympathetic nerves are important for salivary gland biogenesis and regeneration.

Figure 4

Overview of three approaches for salivary gland repair or regeneration: Stem/progenitor cell therapy, gene therapy and gland bioengineering. For stem/progenitor cell therapy a preoperative PET/CT scan, adapted from reference [79], shows the region of the unaffected SMG (arrow) used for a biopsy and the affected submandibular lymph nodes are yellow. Human salispheres are cultured from the biopsy, scale bar = 100 μm. Autologous transplantation of the spheres into the affected salivary gland occurs after therapy. Gland bioengineering involves combining biomaterials with cells to grow an artificial gland, which can be transplanted into a patient. Gene therapy uses viral vectors to transduce genes that repair or improve the secretory function of the gland.