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 nonepithelial cells and/or their bioactive lysates; and (3) tissue engineering approaches using 3D (threedimensional) 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 SIGNIFICANCE STATEMENTThis review covers recent advances in translating cell-based research toward pre-clinical therapies. We focus on salivary gland (SG) loss-of-function and subsequent dry mouth syndrome as caused by radiation therapy or systemic disease, although the described concepts can be translated to other injured somatic tissues. Proposed therapies include implantation of autologous tissue-specific stem/progenitor cells, non-tissue specific cells and/or their bioactive lysates (secretome); and organoid-like constructs created by cells in the presence or not of bioactive cues and three-dimensional biomaterials. These emerging approaches to repair damaged SGs are discussed herein, and evaluated on their success to restore native tissue architecture, epithelial cell polarization, ductal branching, lumen formation, directionality of secretory flow, and clinically relevant tissue functionality.

Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-δ

“…Loss of salivary function following IR occurs more rapidly than can be accounted for by cell turnover alone, and models of “early” and “late” effects of IR have been proposed to explain this conundrum (29). Early effects of IR are seen within the first few weeks and likely result from direct damage to acinar cells resulting in impairment of secretory ability, and the subsequent loss of cells through apoptosis.…”

Cell culture of differentiated human salivary epithelial cells in a serum‐free and scalable suspension system: The salivary functional units model

“…To date, however, the expansion of the enzymatically obtained primary acinar cells to a clinically useful mass and the maintenance of an acinar‐specific maturation state have been the two biggest technological hurdles to overcome in vitro. Thus, research efforts in the past decade have largely focused on identifying tissue‐resident stem cells that can self‐renew (Lombaert et al, ) and/or encapsulating cells in various matrix‐derived scaffolds, in which salivary epithelial cells spontaneously organize into spheroids with acinar‐like properties (Cantara et al, ; Lilliu et al, ; Maria, Liu, El‐Hakim, Zeitouni, & Tran, ; Maria, Zeitouni, Gologan, & Tran, ; Pradhan‐Bhatt et al, ; Soscia et al, ; Srinivasan et al, ).…”

“…Current standard-of-care treatments involving cholinergic agonist drugs are limited by the need for residual salivary acinar cells, whereas treatments using artificial saliva substitutes provide only temporary relief as lubricants (Vissink et al, 2010). Thus, emerging platforms, such as gene and cell-based therapy, are being explored for their utility as disease-modifying therapeutics to restore salivation in xerostomia patients (Baum, Alevizos, Chiorini, Cotrim, & Zheng, 2015;Lombaert, Movahednia, Adine, & Ferreira, 2016).…”

Three‐Dimensional Bioprinting Nanotechnologies towards Clinical Application of Stem Cells and Their Secretome in Salivary Gland Regeneration

“…However, this mouse model system may not fully translate into clinics due to the use of fetal glands. Thus, this major advance prompted researchers to develop 3D organotypic cultures to produce SG organoids or mini-glands that can recapitulate the in vivo native environment and SG morphology and architecture [10]. …”

“…Thus, novel and effective therapeutical strategies for SG hypofunction are required [10]. Due to the depletion of the self-renewable progenitor/stem cell pool during RT damage, cell-based therapies are essential not only to generate new saliva-secreting tissues [10–13] but also to potentially repair the damaged SG via the production and extracellular release of bioactive secretory proteins by transplanted cells [14–17]. This group of non-membrane-bound secretory proteins has been named the salivary secretome [18].…”