Concise Review: Salivary Gland Regeneration: Therapeutic Approaches from Stem Cells to Tissue Organoids

Abstract

The human salivary gland (SG) has an elegant architecture of epithelial acini, connecting ductal branching structures, vascular and neuronal networks that together function to produce and secrete saliva. This review focuses on the translation of cell- and tissue-based research toward therapies for patients suffering from SG hypofunction and related dry mouth syndrome (xerostomia), as a consequence of radiation therapy or systemic disease. We will broadly review the recent literature and discuss the clinical prospects of stem/progenitor cell and tissue-based therapies for SG repair and/or regeneration. Thus far, several strategies have been proposed for the purpose of restoring SG function: (1) transplanting autologous SG-derived epithelial stem/progenitor cells; (2) exploiting non-epithelial cells and/or their bioactive lysates; and (3) tissue engineering approaches using 3D (three-dimensional) biomaterials loaded with SG cells and/or bioactive cues to mimic in vivo SGs. We predict that further scientific improvement in each of these areas will translate to effective therapies toward the repair of damaged glands and the development of miniature SG organoids for the fundamental restoration of saliva secretion. Stem Cells 2017;35:97-105.

Keywords: Organoids; Radiation therapy; Regeneration; Salivary gland; Salivary hypofunction; Stem cells; Transplantation; Xerostomia.

Figure 1.

Different stages of damage in salivary glands evoked by radiation therapy (RT). (1) During salivary gland (SG) tissue homeostasis, glands are innervated and vascularized to support the epithelial compartment that consists of ductal and acinar cells. (1) Upon partial RT damage, parts of the gland are mild to moderately affected by RT (depending on the species), including the acinar compartment. (3) When RT damage globally affects the SG, massive fibrosis with varying degrees of inflammation can be observed with extensive loss in acinar and stem/progenitor cells. The irradiated glandular tissue is further marked by reduced endothelial function and neuronal dysregulation. Abbreviations: RT, radiation therapy; SG, salivary gland.

Figure 2.

Proposed therapies to regenerate radiated salivary glands (SGs). Different epithelial cell types are maintained during homeostasis: ductal (intercalated, striated, granular convoluted tubule, and excretory), myoepithelial, and acinar cells. When glands are partially or globally injured, epithelial cells can undergo apoptosis and/or become functionally damaged. (1a) Reservoir cells of acinar and ductal compartments could then be transplanted post-radiation to locally repair the epithelia. (2a) Similarly, adipocytes, bone marrow (BM)-derived cells, mesenchymal stem cells (MSC) and/or amniotic cells can be transplanted, mobilized or intravenously (i.v.) delivered to aid in repair mechanisms. They can either participate in the formation of glandular cell types or stimulate radiation-surviving cells with their cellular secretome. (1b) After global SG damage, transplantation of multipotent SG specific epithelial stem/progenitors were shown to functionally and morphologically repair the tissue. (2b) Transplants of embryonic stem cells (ESC) and iPS (induced Pluripotent Stem cells) have also been explored to replace lost glandular cell types. (3) When SG are resected, in vitro tissue engineered organoids can be embedded in extracellular matrix and/or biomaterials and placed in the glandular bedding to connect with remaining tissue residues. Abbreviations: BM, bone marrow; MSC, mesenchymal stem cells; ESC, embryonic stem cells.