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.
Human embryonic stem cells (hESCs)-derived keratinocytes hold great clinical and research potential. However, the current techniques are hampered by the use of xenogenic components that limits their clinical application. Here we demonstrated an efficient differentiation of H9 hESCs (H9-hESCs) into keratinocytes (H9-Kert) with the minimum use of animal-derived materials. For differentiation, we established two microenvironment systems originated from H9-hESCs (autogenic microenvironment). These autogenic microenvironment systems consist of an autogenic coculture system (ACC) and an autogenic feeder-free system (AFF). In addition, we showed a stage-specific effect of Activin in promoting keratinocyte differentiation from H9-hESCs while repressing the expression of early neural markers in the ACC system. Furthermore, we also explained the effect of Activin in construction of the AFF system made up of extracellular matrix similar to basement membrane extracted from H9-hESC-derived fibroblasts. H9-Kert differentiated in both systems expressed keratinocyte markers at mRNA and protein levels. H9-Kert were also able to undergo terminal differentiation in high Ca(2+) medium. These findings support the transition toward the establishment of an animal-free microenvironment for successful differentiation of hESCs into keratinocytes for potential clinical application.
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