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Current Topics in Developmental Biology 2015Salivary glands develop as highly branched structures designed to produce and secrete saliva. Advances in mouse genetics, stem cell biology, and regenerative medicine... (Review)
Review
Salivary glands develop as highly branched structures designed to produce and secrete saliva. Advances in mouse genetics, stem cell biology, and regenerative medicine are having a tremendous impact on our understanding of salivary gland organogenesis. Understanding how submandibular gland (SMG) initiation, branching morphogenesis, and cell differentiation occur, as well as defining the progenitor/stem cells and cell and tissue interactions that drive SMG development will help guide regenerative approaches for patients suffering from loss of salivary gland function. This review focuses on recent literature from the past 5 years investigating the regulatory mechanisms driving SMG organogenesis.
Topics: Animals; Cell Differentiation; Epithelium; Fibroblast Growth Factor 10; Gene Expression Regulation, Developmental; Humans; Organogenesis; Salivary Glands; Stem Cells; Submandibular Gland
PubMed: 26589923
DOI: 10.1016/bs.ctdb.2015.07.029 -
Genesis (New York, N.Y. : 2000) May 2018Salivary glands are responsible for maintaining the health of the oral cavity and are routinely damaged by therapeutic radiation for head and neck cancer as well as by... (Review)
Review
Salivary glands are responsible for maintaining the health of the oral cavity and are routinely damaged by therapeutic radiation for head and neck cancer as well as by autoimmune diseases such as Sjögren's syndrome. Regenerative approaches based on the reactivation of endogenous stem cells or the transplant of exogenous stem cells hold substantial promise in restoring the structure and function of these organs to improve patient quality of life. However, these approaches have been hampered by a lack of knowledge on the identity of salivary stem cell populations and their regulators. In this review we discuss our current knowledge on salivary stem cells and their regulators during organ development, homeostasis and regeneration. As increasing evidence in other systems suggests that progenitor cells may be a source of cancer, we also review whether these same salivary stem cells may also be cancer initiating cells.
Topics: Adult Stem Cells; Animals; Cell Differentiation; Humans; Neoplasms; Regeneration; Salivary Glands
PubMed: 29663717
DOI: 10.1002/dvg.23211 -
Oral Diseases Mar 2019Mice are a widely utilized in vivo model for translational salivary gland research but must be used with caution. Specifically, mouse salivary glands are similar in many... (Comparative Study)
Comparative Study Review
Mice are a widely utilized in vivo model for translational salivary gland research but must be used with caution. Specifically, mouse salivary glands are similar in many ways to human salivary glands (i.e., in terms of their anatomy, histology, and physiology) and are both readily available and relatively easy and affordable to maintain. However, there are some significant differences between the two organisms, and by extension, the salivary glands derived from them must be taken into account for translational studies. The current review details pertinent similarities and differences between human and mouse salivary glands and offers practical guidelines for using both for research purposes.
Topics: Animals; Bioengineering; Cytological Techniques; Humans; Mice; Pluripotent Stem Cells; Salivary Glands; Translational Research, Biomedical
PubMed: 29383862
DOI: 10.1111/odi.12840 -
Ear, Nose, & Throat Journal Aug 2020The pathogenesis and molecular basis of salivary gland tumors (SGT) are not well understood. We investigated the expression of receptor activator of nuclear factor κB...
OBJECTIVES
The pathogenesis and molecular basis of salivary gland tumors (SGT) are not well understood. We investigated the expression of receptor activator of nuclear factor κB (RANK) and RANK ligand (RANKL) in benign and malignant SGTs and their relationship with clinicopathological features.
METHODS
Fifty malignant and 38 benign SGTs were analyzed in this study. We evaluated the correlation between RANK and RANKL expression and benign and malignant tumors, as well as the correlation between clinicopathological prognostic parameters and RANK and RANKL expression.
RESULTS
Receptor activator of nuclear factor κB was positive in 82% (41) malignant SGTs and in 34.2% (13) benign SGTs. Receptor activator of nuclear factor κB ligand was expressed in 28% (14) malignant and 5.3% (2) benign tumors. Receptor activator of nuclear factor κB and RANKL expression were significantly different between benign and malignant SGTs ( < .001, = .006, respectively). However, a relationship was not found between positive expression of RANK or RANKL and clinicopathological features.
CONCLUSIONS
In our study, RANK and RANKL expression was found to be higher in malignant SGTs compared to benign SGTs and RANK was more sensitive than RANKL. In addition, RANK and RANKL expression was higher in some malignant histological subtypes. Based on these results, we think that RANK and RANKL expression in SGTs and its potential as a target for treatment should continue to be investigated.
Topics: Aged; Biomarkers, Tumor; Female; Gene Expression; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Grading; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Salivary Gland Neoplasms; Salivary Glands; Sensitivity and Specificity; Tumor Burden
PubMed: 32525717
DOI: 10.1177/0145561320930640 -
Biochimica Et Biophysica Acta.... Nov 2018Salivary glands secrete saliva, a mixture of proteins and fluids, which plays an extremely important role in the maintenance of oral health. Loss of salivary secretion... (Review)
Review
Salivary glands secrete saliva, a mixture of proteins and fluids, which plays an extremely important role in the maintenance of oral health. Loss of salivary secretion causes a dry mouth condition, xerostomia, which has numerous deleterious consequences including opportunistic infections within the oral cavity, difficulties in eating and swallowing food, and problems with speech. Saliva secretion is regulated by stimulation of specific signaling mechanisms within the acinar cells of the gland. Neurotransmitter-stimulated increase in cytosolic [Ca] ([Ca]) in acinar cells is the primary trigger for salivary fluid secretion from salivary glands, the loss of which is a critical factor underlying dry mouth conditions in patients. The increase in [Ca] regulates multiple ion channel and transport activities that together generate the osmotic gradient which drives fluid secretion across the apical membrane. Ca entry mediated by the Store-Operated Ca Entry (SOCE) mechanism provides the essential [Ca] signals to trigger salivary gland fluid secretion. Under physiological conditions depletion of ER-Ca stores is caused by activation of IP3R by IP3 and this provides the stimulus for SOCE. Core components of SOCE in salivary gland acinar cells are the plasma membrane Ca channels, Orai1 and TRPC1, and STIM1, a Ca-sensor protein in the ER, which regulates both channels. In addition, STIM2 likely enhances the sensitivity of cells to ER-Ca depletion thereby tuning the cellular response to agonist stimulation. Two major, clinically relevant, conditions which cause irreversible salivary gland dysfunction are radiation treatment for head-and-neck cancers and the autoimmune exocrinopathy, Sjögren's syndrome (pSS). However, the exact mechanism(s) that causes the loss of fluid secretion, in either condition, is not clearly understood. A number of recent studies have identified that defects in critical Ca signaling mechanisms underlie salivary gland dysfunction caused by radiation treatment or Sjögren's syndrome (pSS). This chapter will discuss these very interesting and important studies.
Topics: Acinar Cells; Animals; Calcium; Calcium Channels; Calcium Signaling; Disease Susceptibility; Humans; Intracellular Space; Neurotransmitter Agents; Saliva; Salivary Glands
PubMed: 30006140
DOI: 10.1016/j.bbamcr.2018.07.002 -
Current Protocols in Immunology Dec 2020Sjögren's syndrome (SS) is a systemic autoimmune disease affecting multiple organ systems. Salivary and lacrimal gland involvement cause dry mouth and dry eye and are...
Sjögren's syndrome (SS) is a systemic autoimmune disease affecting multiple organ systems. Salivary and lacrimal gland involvement cause dry mouth and dry eye and are the most common clinical presentations of the disease. Patients with SS also have autoantibodies targeting multiple nuclear and cytoplasmic antigens. Innate immune activation plays a critical role in SS pathogenesis. This article describes the activation of specific innate immune pathways in mice to study SS salivary gland manifestations. Methodologies for evaluating salivary gland inflammation and salivary function are described. This article also describes protocols for in-house assays to measure autoantibody titers in serum. © 2020 Wiley Periodicals LLC Basic Protocol 1: Acceleration of Sjögren's syndrome by activating the toll-like receptor 3 pathway Basic Protocol 2: Induction of Sjögren's syndrome by activating the stimulator of interferon genes pathway Alternate Protocol: Acceleration of Sjögren's syndrome by the administration of Freund's incomplete adjuvant Support Protocol 1: Evaluating salivary gland function Support Protocol 2: Evaluating salivary gland inflammation Support Protocol 3: Measuring autoantibody titers by indirect immunofluorescence.
Topics: Animals; Cell Culture Techniques; Humans; Immunity, Innate; Inflammation; Interferons; Mice; Models, Animal; Salivary Glands; Sjogren's Syndrome
PubMed: 33252847
DOI: 10.1002/cpim.114 -
International Journal of Molecular... May 2021Aging-related salivary dysfunction commonly induces the poor oral health, including decreased saliva flow and dental caries. Although the clinical significance of the... (Meta-Analysis)
Meta-Analysis Review
Aging-related salivary dysfunction commonly induces the poor oral health, including decreased saliva flow and dental caries. Although the clinical significance of the salivary glands is well-known, the complex metabolic pathways contributing to the aging-dysfunction process are only beginning to be uncovered. Here, we provide a comprehensive overview of the metabolic changes in aging-mediated salivary gland dysfunction as a key aspect of oral physiology. Several metabolic neuropeptides or hormones are involved in causing or contributing to salivary gland dysfunction, including hyposalivation and age-related diseases. Thus, aging-related metabolism holds promise for early diagnosis, increased choice of therapy and the identification of new metabolic pathways that could potentially be targeted in salivary gland dysfunction.
Topics: Aging; Animals; Biomarkers; Disease Management; Disease Susceptibility; Energy Metabolism; Hormones; Humans; Metabolomics; Saliva; Salivary Gland Diseases; Salivary Glands
PubMed: 34072470
DOI: 10.3390/ijms22115835 -
Seminars in Cell & Developmental Biology 2014The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review will focus on research on mouse submandibular... (Review)
Review
The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review will focus on research on mouse submandibular gland development and the translation of this basic research toward therapy for patients suffering from salivary hypofunction. Here we review the most recent literature that has enabled a better understanding of the mechanisms of salivary gland development. Additionally, we discuss approaches proposed to restore salivary function using gene and cell-based therapy. Increasing our understanding of the developmental mechanisms involved during development is critical to design effective therapies for regeneration and repair of damaged glands.
Topics: Animals; Cell Growth Processes; Humans; Mice; Morphogenesis; Regeneration; Salivary Glands; Stem Cells
PubMed: 24333774
DOI: 10.1016/j.semcdb.2013.12.001 -
Journal of Dental Research Oct 2019Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune... (Review)
Review
Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren's syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.
Topics: Animals; Cell Lineage; Epithelial Cells; Keratins; Mice; SOX Transcription Factors; Salivary Glands; Signal Transduction; Trans-Activators
PubMed: 31331226
DOI: 10.1177/0022034519864592 -
Current Protocols in Cell Biology Jun 2019Organoids are important research tools for studying organ morphogenesis and differentiation because they recapitulate ex vivo the native 3D organization of cells that is...
Organoids are important research tools for studying organ morphogenesis and differentiation because they recapitulate ex vivo the native 3D organization of cells that is essential for proper cell and organ function. The composition of organoids can be manipulated to incorporate specific cell types to facilitate molecular interrogation of cell-cell interactions during organoid formation. A method for generating organoids derived from both embryonic salivary gland epithelial progenitor cells and mesenchymal support cells is described. Methods for isolating enriched populations of the epithelial cells as clusters and the mesenchyme cells as single cells from mouse embryonic submandibular salivary glands are also provided. Separating the epithelial and mesenchymal cell populations allows for independent molecular manipulation of each cell type. In addition, methods for lentiviral transduction of the mesenchyme cells and quantitative image analysis of organoids are provided. The methods described here are useful for exploring mechanisms driving organ formation. © 2018 by John Wiley & Sons, Inc.
Topics: Animals; Cell Lineage; Epithelial Cells; Mesoderm; Mice; Organoids; Salivary Glands; Tissue Culture Techniques
PubMed: 30394683
DOI: 10.1002/cpcb.76