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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 -
PloS One 2022Mammary gland is present in all mammals and usually functions in producing milk to feed the young offspring. Mammogenesis refers to the growth and development of mammary...
Mammary gland is present in all mammals and usually functions in producing milk to feed the young offspring. Mammogenesis refers to the growth and development of mammary gland, which begins at puberty and ends after lactation. Pregnancy is regulated by various cytokines, which further contributes to mammary gland development. Epithelial cells, including basal and luminal cells, are one of the major components of mammary gland cells. The development of basal and luminal cells has been observed to significantly differ at different stages. However, the underlying mechanisms for differences between basal and luminal cells have not been fully studied. To explore the mechanisms underlying the differentiation of mammary progenitors or their offspring into luminal and myoepithelial cells, the single-cell sequencing data on mammary epithelia cells of virgin and pregnant mouse was deeply investigated in this work. We evaluated features by using Monte Carlo feature selection and plotted the incremental feature selection curve with support vector machine or RIPPER to find the optimal gene features and rules that can divide epithelial cells into four clusters with different cell subtypes like basal and luminal cells and different phases like pregnancy and virginity. As representations, the feature genes Cldn7, Gjb6, Sparc, Cldn3, Cited1, Krt17, Spp1, Cldn4, Gjb2 and Cldn19 might play an important role in classifying the epithelial mammary cells. Notably, seven most important rules based on the combination of cell-specific and tissue-specific expressions of feature genes effectively classify the epithelial mammary cells in a quantitative and interpretable manner.
Topics: Animals; Cell Differentiation; Epithelial Cells; Female; Lactation; Mammals; Mammary Glands, Animal; Mice; Pregnancy; Sexual Maturation
PubMed: 35486595
DOI: 10.1371/journal.pone.0267211 -
Head and Neck Pathology Mar 2023Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity,... (Review)
Review
BACKGROUND
Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity, potentially creating diagnostic dilemmas in various organ systems. In the head and neck, clear cell change can occur in lesions of salivary, odontogenic, thyroid, parathyroid, or sinonasal/skull base origin, as well as in metastases to these regions.
METHODS
This review elaborates the top ten clear cell lesions in the head and neck, emphasizing their distinguishing histologic, immunohistochemical, and molecular attributes, and presents a rational approach to arriving at an accurate classification.
RESULTS
Cytoplasmic pallor or clearing may be caused by accumulations of glycogen, lipid, mucin, mucopolysaccharides, water, foreign material, hydropic organelles, or immature zymogen granules. Overlapping morphologic features may present a diagnostic challenge to the surgical pathologist. Similarity in immunohistochemical profiles, often due to common cell type, as well as rare non-neoplastic mimics, furthers the diagnostic conundrum.
CONCLUSIONS
The top ten lesions reviewed in this article are as follows: (1) clear cell carcinoma (salivary and odontogenic), (2) mucoepidermoid carcinoma, (3) myoepithelial and epithelial-myoepithelial carcinoma, (4) oncocytic salivary gland lesions, (5) squamous cell carcinoma, (6) parathyroid water clear cell adenoma, (7) metastatic renal cell carcinoma (especially in comparison to clear cell thyroid neoplasms), (8) sinonasal renal cell-like adenocarcinoma, (9) chordoma, and (10) rhinoscleroma.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Epithelial Cells; Carcinoma, Squamous Cell; Adenocarcinoma, Clear Cell; Salivary Gland Neoplasms
PubMed: 36928734
DOI: 10.1007/s12105-022-01518-6 -
Cellular and Molecular Life Sciences :... Apr 2021The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian... (Review)
Review
The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian salivary gland development, particularly on the differentiation of acinar, ductal, and myoepithelial cells. We discuss recent studies that provide conceptual advances in the understanding of the molecular mechanisms of salivary gland development. In addition, we describe the organogenesis of submandibular glands (SMGs), model systems used for the study of SMG development, and the key signaling pathways as well as cellular processes involved in salivary gland development. The findings from the recent studies elucidating the identity of stem/progenitor cells in the SMGs, and the process by which they are directed along a series of cell fate decisions to form functional glands, are also discussed. Advances in genetic tools and tissue engineering strategies will significantly increase our knowledge about the mechanisms by which signaling pathways and cells establish tissue architecture and function during salivary gland development, which may also be conserved in the growth and development of other organ systems. An increased knowledge of organ development mechanisms will have profound implications in the design of therapies for the regrowth or repair of injured tissues. In addition, understanding how the processes of cell survival, expansion, specification, movement, and communication with neighboring cells are regulated under physiological and pathological conditions is critical to the development of future treatments.
Topics: Animals; Cell Differentiation; Humans; Organogenesis; Salivary Glands; Signal Transduction; Stem Cells
PubMed: 33449148
DOI: 10.1007/s00018-020-03741-2 -
Endocrinology May 2008Normal mammary gland development requires the coordinated proliferation and morphogenesis of both mammary luminal epithelial cells (LECs) and myoepithelial cells (MECs)....
Normal mammary gland development requires the coordinated proliferation and morphogenesis of both mammary luminal epithelial cells (LECs) and myoepithelial cells (MECs). Cell proliferation in cultured mammary organoids containing both LECs and MECs is not increased by progestin (R5020) or 17beta-estradiol (E2) alone or R5020+E2 but is increased by E2-regulated, mammary stroma-derived Hepatocyte growth factor (HGF) and further increased by HGF+R5020. We investigated the effects of HGF and/or R5020 on morphology and LEC- and MEC-specific in vitro proliferation in organoids. HGF-induced tubulogenesis was initiated and carried out by LECs starting with cellular extensions, followed by the formation of chains and cords, and culminating in tubule formation. MECs did not appear to have an active role in this process. Whereas HGF by itself caused maximal proliferation of LECs, HGF+R5020 produced a synergistic and specific increase in MEC proliferation. Because only LECs expressed progesterone receptors (PRs), we investigated the role of receptor activator of nuclear factor-kappaB ligand (RANKL), a progestin-induced paracrine factor, in mediating increased MEC proliferation. Quantitative RT-PCR showed that RANKL mRNA was induced by R5020 or HGF+R5020 and RANKL protein colocalized with PRs in LECs. The increased proliferation of MECs in response to HGF+R5020 could be blocked by neutralizing antibody to RANKL and reproduced by treatment with HGF plus exogenous RANKL in place of R5020. Neither R5020, nor exogenously administered RANKL increased proliferation of LECs. These results led us to conclude that RANKL, induced by progestin in PR-positive cells, is secreted and interacts with HGF to specifically increase proliferation of PR-negative MECs.
Topics: Animals; Cell Proliferation; Cells, Cultured; Drug Combinations; Epithelial Cells; Female; Hepatocyte Growth Factor; Mammary Glands, Animal; Mice; Mice, Inbred BALB C; Muscle Cells; Organ Culture Techniques; Organoids; Paracrine Communication; Progesterone Congeners; Progestins; Promegestone; Protein Isoforms; Proto-Oncogene Proteins c-met; RANK Ligand; Receptors, Progesterone
PubMed: 18218689
DOI: 10.1210/en.2007-1398 -
Journal of Cellular Biochemistry Jul 2017To improve the precision of molecular diagnosis and to develop and guide targeted therapies of breast cancer, it is essential to determine the mechanisms that underlie... (Review)
Review
To improve the precision of molecular diagnosis and to develop and guide targeted therapies of breast cancer, it is essential to determine the mechanisms that underlie the specific tumor phenotypes. To this end, the application of a snapshot of gene expression profile for breast cancer diagnosis and prognosis is fundamentally challenged since the tissue-based data are derived from heterogonous cell types and are not likely to reflect the dynamics of context-dependent tumor progression and drug sensitivity. The intricate network of epithelial differentiation program can be concertedly controlled by tumor suppressor maspin, a homologue of clade B serine protease inhibitors (serpin), through its multifaceted molecular interactions in multiple subcellular localizations. Unlike most other serpins that are expressed in multiple cell types, maspin is epithelial specific and has distinct roles in luminal and myoepithelial cells. Endogenously expressed maspin has been found in the nucleus and cytoplasm, and detected on the surface of cell membrane. It is also secreted free and as an exosomal cargo protein. Research in the field has led to the identification of the maspin targets and maspin-associated molecules, as well as the structural determinants of its suppressive functions. The current review discusses the possibility for maspin to serve as a cell type-specific and context-sensitive marker to improve the precision of breast cancer diagnosis and prognosis. These advancements further suggest a new window of opportunity for designing novel maspin-based chemotherapeutic agents with improved anti-cancer potency. J. Cell. Biochem. 118: 1639-1647, 2017. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Breast Neoplasms; Epithelial Cells; Humans; Mammary Glands, Human; Precision Medicine; Serpins
PubMed: 28262971
DOI: 10.1002/jcb.25969 -
Biochimica Et Biophysica Acta.... Jan 2022Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known... (Review)
Review
Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known about how milk is produced and how it is ejected from the lumen of mammary alveoli and ducts. This review focuses on the latter. We discuss how a relatively small number of basal cells, wrapping around each alveolar unit, contract to forcibly expel milk from the alveolar lumen. We consider how individual basal cells coordinate their activity, the fate of these cells at the end of lactation and avenues for future deliberation and exploration.
Topics: Animals; Cell Plasticity; Epithelial Cells; Female; Humans; Lactation; Mammary Glands, Human
PubMed: 34653580
DOI: 10.1016/j.bbamcr.2021.119159 -
Scientific Reports Jan 2024Salivary gland myoepithelial cells regulate saliva secretion and have been implicated in the histological diversity of salivary gland tumors. However, detailed...
Salivary gland myoepithelial cells regulate saliva secretion and have been implicated in the histological diversity of salivary gland tumors. However, detailed functional analysis of myoepithelial cells has not been determined owing to the few of the specific marker to isolate them. We isolated myoepithelial cells from the submandibular glands of adult mice using the epithelial marker EpCAM and the cell adhesion molecule CD49f as indicators and found predominant expression of the transcription factor FoxO1 in these cells. RNA-sequence analysis revealed that the expression of cell cycle regulators was negatively regulated in FoxO1-overexpressing cells. Chromatin immunoprecipitation analysis showed that FoxO1 bound to the p21/p27 promoter DNA, indicating that FoxO1 suppresses cell proliferation through these factors. In addition, FoxO1 induced the expression of ectodysplasin A (Eda) and its receptor Eda2r, which are known to be associated with X-linked hypohidrotic ectodermal dysplasia and are involved in salivary gland development in myoepithelial cells. FoxO1 inhibitors suppressed Eda/Eda2r expression and salivary gland development in primordial organ cultures after mesenchymal removal. Although mesenchymal cells are considered a source of Eda, myoepithelial cells might be one of the resources of Eda. These results suggest that FoxO1 regulates myoepithelial cell proliferation and Eda secretion during salivary gland development in myoepithelial cells.
Topics: Animals; Mice; Ectodysplasins; Epithelial Cells; Receptors, Tumor Necrosis Factor; Salivary Gland Neoplasms; Submandibular Gland; Transcription Factors; Xedar Receptor
PubMed: 38212454
DOI: 10.1038/s41598-024-51619-1 -
Journal of Mammary Gland Biology and... Jul 2005The human breast epithelium is a branching ductal system composed of an inner layer of polarized luminal epithelial cells and an outer layer of myoepithelial cells that... (Review)
Review
The human breast epithelium is a branching ductal system composed of an inner layer of polarized luminal epithelial cells and an outer layer of myoepithelial cells that terminate in distally located terminal duct lobular units (TDLUs). While the luminal epithelial cell has received the most attention as the functionally active milk-producing cell and as the most likely target cell for carcinogenesis, attention on myoepithelial cells has begun to evolve with the recognition that these cells play an active part in branching morphogenesis and tumor suppression. A major question that has been the subject of investigation pertains to how the luminal epithelial and myoepithelial lineages are related and precisely how they arise from a common putative stem cell population within the breast. Equally important is the question of how heterotypic signaling occurs between luminal epithelial and surrounding myoepithelial cells in normal breast morphogenesis and neoplasia. In this review we discuss data from our laboratories and from others regarding the cellular origin of human myoepithelial cells, their function in maintaining tissue polarity in the normal breast, and their role during neoplasia.
Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Polarity; Cell Transformation, Neoplastic; Epithelial Cells; Female; Humans; Mammary Glands, Human; Morphogenesis; Stem Cells
PubMed: 16807805
DOI: 10.1007/s10911-005-9586-4 -
The Journal of Cell Biology Aug 2019In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and... (Review)
Review
In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer cells facilitating protease-independent BM invasion. Moreover, collective cell interactions, proliferation, cancer-associated fibroblasts, myoepithelial cells, and immune cells are all implicated in regulating BM invasion through physical forces. A comprehensive understanding of BM structure and mechanics and diverse modes of BM invasion may yield new strategies for blocking cancer progression and metastasis.
Topics: Animals; Basement Membrane; Biomechanical Phenomena; Cell Communication; Humans; Neoplasm Invasiveness; Neoplasms; Peptide Hydrolases
PubMed: 31315943
DOI: 10.1083/jcb.201903066