Building a Functional Salivary Gland for Cell-Based Therapy: More than Secretory Epithelial Acini

Barrows, Caitlynn M.; Wu, Danielle; Farach‐Carson, Mary C.; Young, Simon

doi:10.1089/ten.tea.2020.0184

Cited by 14 publications

(26 citation statements)

References 175 publications

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“…Previous studies by other groups have also observed dead cells and positive caspase-3 staining in the center of the acini-like structures when cultur-ing salivary gland progenitor cells in various hydrogels. [20,27,[40][41][42][43] Cavities with varying number and size were observed by day 14 (Figure 3D,E), but they cannot be designated as lumens, as it is unclear how or when they are formed and whether they are polarized differently from the outer cell layer. We speculate that cells on the inside of the spheres may undergo apoptosis because they are excluded from cell-cell contacts found on the outside of the sphere.…”

Section: Formation Of Sgm Within Hydrogel Microenvironmentsmentioning

confidence: 99%

Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)‐Degradable Hydrogels to Maintain Tissue Structure and Function

Song

Sharipol

Uchida

et al. 2022

Adv Healthcare Materials

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Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro. To reduce the precipitous loss of secretory function, a modified approach to isolate intact acinar cell clusters and intercalated ducts (AIDUCs), rather than commonly used single cell suspension, is investigated. This isolation approach yields AIDUCs that maintain many of the cell-cell and cell-matrix interactions of intact glands. Encapsulation of AIDUCs in matrix metalloproteinase (MMP)-degradable PEG hydrogels promotes self-assembly into salivary gland mimetics (SGm) with acinar-like structure. Expression of Mist1, a transcription factor associated with secretory function, is detectable throughout the in vitro culture period up to 14 days. Immunohistochemistry also confirms expression of acinar cell markers (NKCC1, PIP and AQP5), duct cell markers (K7 and K5), and myoepithelial cell markers (SMA). Robust carbachol and ATP-stimulated calcium flux is observed within the SGm for up to 14 days after encapsulation, indicating that secretory function is maintained. Though some acinar-to-ductal metaplasia is observed within SGm, it is reduced compared to previous reports. In conclusion, cell-cell interactions maintained within AIDUCs together with the hydrogel microenvironment may be a promising platform for salivary gland regenerative strategies.

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Section: Formation Of Sgm Within Hydrogel Microenvironmentsmentioning

confidence: 99%

Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)‐Degradable Hydrogels to Maintain Tissue Structure and Function

Song

Sharipol

Uchida

et al. 2022

Adv Healthcare Materials

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“…In 1999, Bruce Baum and colleagues indicated three significant ways to re-engineer salivary epithelial cell functions: redesigning secretory function, repairing hypofunctional SG, and developing artificial SG [ 10 ]. Since then, various tissue engineering strategies have been conducted to restore salivation, and some have led to clinical trials [ 11 – 19 ]. Indeed, clinical trials suggest stem cell therapy [ 16 , 17 , 19 ] combined with special cell culture methods such as spontaneous cell aggregation, hanging drop and rotating culture vessels [ 1 , 20 , 21 ] or scaffold material [ 22 – 25 ] to produce functional secretory epithelial organoids, and gene therapy [ 18 ] may offer new therapeutic options for radiation-induced xerostomia.…”

Section: Introductionmentioning

confidence: 99%

Bioengineering in salivary gland regeneration

et al. 2022

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Salivary gland (SG) dysfunction impairs the life quality of many patients, such as patients with radiation therapy for head and neck cancer and patients with Sjögren’s syndrome. Multiple SG engineering strategies have been considered for SG regeneration, repair, or whole organ replacement. An in-depth understanding of the development and differentiation of epithelial stem and progenitor cells niche during SG branching morphogenesis and signaling pathways involved in cell–cell communication constitute a prerequisite to the development of suitable bioengineering solutions. This review summarizes the essential bioengineering features to be considered to fabricate an engineered functional SG model using various cell types, biomaterials, active agents, and matrix fabrication methods. Furthermore, recent innovative and promising approaches to engineering SG models are described. Finally, this review discusses the different challenges and future perspectives in SG bioengineering.

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

Alginate Hydrogel Microtubes for Salivary Gland Cell Organization and Cavitation

et al. 2022

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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.

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Building a Functional Salivary Gland for Cell-Based Therapy: More than Secretory Epithelial Acini

Cited by 14 publications

References 175 publications

Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)‐Degradable Hydrogels to Maintain Tissue Structure and Function

Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)‐Degradable Hydrogels to Maintain Tissue Structure and Function

Bioengineering in salivary gland regeneration

Alginate Hydrogel Microtubes for Salivary Gland Cell Organization and Cavitation

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