Abstract
Understanding the different regulatory functions of epithelial and mesenchymal cell types in salivary gland development and cellular organization is essential for proper organoid formation and salivary gland tissue regeneration. Here, we demonstrate a biocompatible platform using pre-formed alginate hydrogel microtubes to facilitate direct epithelial–mesenchymal cell interaction for 3D salivary gland cell organization, which allows for monitoring cellular organization while providing a protective barrier from cell-cluster loss during medium changes. Using mouse salivary gland ductal epithelial SIMS cells as the epithelial model cell type and NIH 3T3 fibroblasts or primary E16 salivary mesenchyme cells as the stromal model cell types, self-organization from epithelial–mesenchymal interaction was examined. We observed that epithelial and mesenchymal cells undergo aggregation on day 1, cavitation by day 4, and generation of an EpCAM-expressing epithelial cell layer as early as day 7 of the co-culture in hydrogel microtubes, demonstrating the utility of hydrogel microtubes to facilitate heterotypic cell–cell interactions to form cavitated organoids. Thus, pre-formed alginate microtubes are a promising co-culture method for further understanding epithelial and mesenchymal interaction during tissue morphogenesis and for future practical applications in regenerative medicine.
Highlights
Research in therapeutic tissue engineering for salivary gland regeneration has demonstrated that a tremendous amount of discovery is still needed before we can successfully replicate the in vivo environment within tissue constructs [1,2]
We examined the feasibility of using alginate hydrogel microtubes to provide a compliant environment with curvature as a bioengineering approach to facilitate 3D salivary gland epithelial–mesenchymal cell interactions and cellular organization
To test the feasibility of using alginate hydrogel microtubes to facilitate 3D cellular organization of salivary gland epithelial and mesenchymal cells, we chose to fabricate hydrogel microtubes with an inner diameter larger than 500 μm, which allows formation of larger cell clusters and organoids and a wall thickness of ~200 μm, which is within the diffusion limit of oxygen and allows cells to have access to sufficient nutrients [40]
Summary
Research in therapeutic tissue engineering for salivary gland regeneration has demonstrated that a tremendous amount of discovery is still needed before we can successfully replicate the in vivo environment within tissue constructs [1,2]. A sustainable and reproducible method for developing functional salivary gland tissue is needed to address both xerostomia, or the feeling of dry mouth, which is a common clinical symptom arising from low saliva output, and hyposalivation [3]. The most common conditions in which hyposalivation and xerostomia occur include: Sjögren’s syndrome, diabetes, radiotherapy for head and neck cancers, salivary gland cancers, side effects due to medication, and aging [3,4,5]. Radiotherapy, which causes irreversible damage to the acini found in the salivary gland, will require some form of tissue transplantation after the fractionated radiation therapy (i.e., multiple treatments over time) has been completed and the body has healed [5].
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