Functional salivary gland regeneration by transplantation of a bioengineered organ germ

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.

A-fodrinAutoantigen Detection in Saliva and on Salivary Ductal Cells in Sjögren Syndrome

“…Such cleaved products could then be presented to ductal epithelial or endothelial cells, which express HLA-DR antigens or CD40, and could then undergo antigen processing. This could result in an immune response with T cell proliferation and the production of the autoantibodies detected in many SS patients [21].This observation also provides a possible explanation for a central role of epithelial cells in SS implied by the location of the periductal and perivascular location of lymphocytic infiltrates in salivary gland ducts and vessels [21,27].It is interesting that cleaved PARP fragments have been reported on the ducts and acini but minimally detected in the area of the lymphocytic infiltrate compared with α-fodrin [11]. This is consistent with the proposal that PARP, a nuclear antigen, we have shown is not expressed on the cell surface during apoptosis and therefore not expected to undergo antigen processing by infiltrating lymphocytes [7].…”

Roles of innervation in developing and regenerating orofacial tissues

“…Proper innervation is also needed to obtain fully functional organs. Bioengineered salivary glands, for example, require specific innervation from parasympathetic, sympathetic and afferent fibres in order to respond correctly to stimuli and produce saliva [68]. However, the vast majority of research on regenerative medicine has neglected the important role of innervation in the regulation of the stem cell fate and behaviour after transplantation.…”

Human development, heredity and evolution

“…Takashi Tsuji (RIKEN CDB, Japan) introduced bioengineered organ germs by combining mouse embryonic mesenchyme and epithelia in a tiny droplet in collagen gel and transplanting these into host animals. He reported successful generation of teeth, hair and salivary glands (Ogawa et al, 2013;Takagi et al, 2016;Yamamoto et al, 2016). Importantly, these tissues have functional nerve connections to the host animals.…”