Abstract
Salivary gland hypofunction, also known as xerostomia, occurs as a result of radiation therapy for head cancer, Sjögren’s syndrome or aging, and can cause a variety of critical oral health issues, including dental decay, bacterial infection, mastication dysfunction, swallowing dysfunction and reduced quality of life. Here we demonstrate the full functional regeneration of a salivary gland that reproduces the morphogenesis induced by reciprocal epithelial and mesenchymal interactions through the orthotopic transplantation of a bioengineered salivary gland germ as a regenerative organ replacement therapy. The bioengineered germ develops into a mature gland through acinar formations with a myoepithelium and innervation. The bioengineered submandibular gland produces saliva in response to the administration of pilocarpine and gustatory stimulation by citrate, protects against oral bacterial infection and restores normal swallowing in a salivary gland-defective mouse model. This study thus provides a proof-of-concept for bioengineered salivary gland regeneration as a potential treatment of xerostomia.
Highlights
Salivary gland hypofunction, known as xerostomia, occurs as a result of radiation therapy for head cancer, Sjogren’s syndrome or aging, and can cause a variety of critical oral health issues, including dental decay, bacterial infection, mastication dysfunction, swallowing dysfunction and reduced quality of life
Terminal bulb cells differentiate into intercalated duct cells and are stored as stem cells to develop into acinar, myoepithelial and duct cells[7]
Our recent studies have provided proofsof-concept that fully functional regeneration of ectodermal organs such as teeth and hair follicles can be achieved by the transplantation of bioengineered organ germs that were reconstituted by our organ germ method[25], in organ replacement regenerative therapy[25,26,27]
Summary
Generation of a bioengineered salivary gland germ. We first investigated whether each bioengineered salivary gland germ, including the parotid, submandibular and sublingual glands, has the ability to regenerate into mature glands using our previously developed organ germ method (Fig. 1a)[25]. In a bioengineered submandibular gland germ that was reconstituted from green fluorescence protein (GFP) mice-derived epithelial cells and normal mice-derived mesenchymal cells, the correct duct connection, the GFP-positive duct of the bioengineered salivary gland and the non-fluorescence parotid duct in the recipient mice were confirmed (Fig. 2e). The wet weights of the bioengineered submandibular (median: 4.0 mg, minimum (min): 1.0 mg, maximum (max): 16.8 mg) and sublingual glands (median: 3.1 mg, min: 1.0 mg, max: 12.0 mg) were relatively low compared with the weights of the natural submandibular (median: 34.7 mg, min: 33.6 mg, max: 35.9 mg) and sublingual glands (median: 6.1 mg, min: 5.8 mg, max: 8.7 mg; Fig. 2h) These results indicate that the bioengineered salivary gland developed with properties corresponding to the origins of the stem cells isolated from embryonic organ germs. Saliva secretion is an essential role of salivary glands for maintaining
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