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Developmental Cell Jul 2013Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent... (Review)
Review
Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent studies suggest that acinar cells, the most abundant cell type in the pancreas, are facultative progenitors capable of reverting to embryonic-like multipotent progenitor cells under injury conditions associated with inflammation. In parallel, it is becoming apparent that within the endocrine pancreas, hormone-producing cells can lose or switch their identity under metabolic stress or in response to single gene mutations. This new view of pancreas dynamics suggests interesting links between pancreas regeneration and pathologies including diabetes and pancreatic cancer.
Topics: Acinar Cells; Carcinoma, Pancreatic Ductal; Cell Death; Cell Dedifferentiation; Cell Differentiation; Cellular Reprogramming; Endocrine Cells; Humans; Pancreas; Pancreatitis; Regeneration; Stem Cells
PubMed: 23867225
DOI: 10.1016/j.devcel.2013.06.013 -
Development (Cambridge, England) Jun 2013Insulin-secreting pancreatic β-cells are essential regulators of mammalian metabolism. The absence of functional β-cells leads to hyperglycemia and diabetes, making... (Review)
Review
Insulin-secreting pancreatic β-cells are essential regulators of mammalian metabolism. The absence of functional β-cells leads to hyperglycemia and diabetes, making patients dependent on exogenously supplied insulin. Recent insights into β-cell development, combined with the discovery of pluripotent stem cells, have led to an unprecedented opportunity to generate new β-cells for transplantation therapy and drug screening. Progress has also been made in converting terminally differentiated cell types into β-cells using transcriptional regulators identified as key players in normal development, and in identifying conditions that induce β-cell replication in vivo and in vitro. Here, we summarize what is currently known about how these strategies could be utilized to generate new β-cells and highlight how further study into the mechanisms governing later stages of differentiation and the acquisition of functional capabilities could inform this effort.
Topics: Acinar Cells; Animals; Cell Differentiation; Cell Proliferation; Cell Transdifferentiation; Cellular Reprogramming; Diabetes Mellitus; Endoderm; Glucagon-Secreting Cells; Glucose; Humans; Insulin Resistance; Insulin-Secreting Cells; Pluripotent Stem Cells
PubMed: 23715541
DOI: 10.1242/dev.093187 -
Journal of Dental Research Jul 2022Current treatments for xerostomia/dry mouth are palliative and largely ineffective. A permanent clinical resolution is being developed to correct hyposalivation using...
Current treatments for xerostomia/dry mouth are palliative and largely ineffective. A permanent clinical resolution is being developed to correct hyposalivation using implanted hydrogel-encapsulated salivary human stem/progenitor cells (hS/PCs) to restore functional salivary components and increase salivary flow. Pluripotent epithelial cell populations derived from hS/PCs, representing a basal stem cell population in tissue, can differentiate along either secretory acinar or fluid-transporting ductal lineages. To develop tissue-engineered salivary gland replacement tissues, it is critical to reliably identify cells in tissue and as they enter these alternative lineages. The secreted protein α-amylase, the transcription factor MIST1, and aquaporin-5 are typical markers for acinar cells, and K19 is the classical ductal marker in salivary tissue. We found that early ductal progenitors derived from hS/PCs do not express K19, and thus earlier markers were needed to distinguish these cells from acinar progenitors. Salivary ductal cells express distinct polarity complex proteins that we hypothesized could serve as lineage biomarkers to distinguish ductal cells from acinar cells in differentiating hS/PC populations. Based on our studies of primary salivary tissue, both parotid and submandibular glands, and differentiating hS/PCs, we conclude that the apical marker MUC1 along with the polarity markers INADL/PATJ and SCRIB reliably can identify ductal cells in salivary glands and in ductal progenitor populations of hS/PCs being used for salivary tissue engineering. Other markers of epithelial maturation, including E-cadherin, ZO-1, and partition complex component PAR3, are present in both ductal and acinar cells, where they can serve as general markers of differentiation but not lineage markers.
Topics: Acinar Cells; Biomarkers; Cell Differentiation; Cells, Cultured; Epithelial Cells; Humans; Membrane Proteins; Mucin-1; Salivary Glands; Tight Junction Proteins; Tumor Suppressor Proteins; Xerostomia
PubMed: 35259994
DOI: 10.1177/00220345221076122 -
Genes To Cells : Devoted To Molecular &... Sep 2021There are currently no treatments for salivary gland diseases, making it vital to understand signaling mechanisms operating in acinar and ductal cells so as to develop...
There are currently no treatments for salivary gland diseases, making it vital to understand signaling mechanisms operating in acinar and ductal cells so as to develop regenerative therapies. To date, little work has focused on elucidating the signaling cascades controlling the differentiation of these cell types in adult mammals. To analyze the function of the Hippo-TAZ/YAP1 pathway in adult mouse salivary glands, we generated adMOB1DKO mice in which both MOB1A and MOB1B were TAM-inducibly deleted when the animals were adults. Three weeks after TAM treatment, adMOB1DKO mice exhibited smaller submandibular glands (SMGs) than controls with a decreased number of acinar cells and an increased number of immature dysplastic ductal cells. The mutants suffered from reduced saliva production accompanied by mild inflammatory cell infiltration and fibrosis in SMGs, similar to the Sjogren's syndrome. MOB1-deficient acinar cells showed normal proliferation and apoptosis but decreased differentiation, leading to an increase in acinar/ductal bilineage progenitor cells. These changes were TAZ-dependent but YAP1-independent. Biochemically, MOB1-deficient salivary epithelial cells showed activation of the TAZ/YAP1 and β-catenin in ductal cells, but reduced SOX2 and SOX10 expression in acinar cells. Thus, Hippo-TAZ signaling is critical for proper ductal and acinar cell differentiation and function in adult mice.
Topics: Acinar Cells; Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; SOXB1 Transcription Factors; Salivary Glands; beta Catenin
PubMed: 34142411
DOI: 10.1111/gtc.12879 -
Bulletin of Mathematical Biology Feb 2021Saliva is secreted from the acinar cells of the salivary glands, using mechanisms that are similar to other types of water-transporting epithelial cells. Using a... (Review)
Review
Saliva is secreted from the acinar cells of the salivary glands, using mechanisms that are similar to other types of water-transporting epithelial cells. Using a combination of theoretical and experimental techniques, over the past 20 years we have continually developed and modified a quantitative model of saliva secretion, and how it is controlled by the dynamics of intracellular calcium. However, over approximately the past 5 years there have been significant developments both in our understanding of the underlying mechanisms and in the way these mechanisms should best be modelled. Here, we review the traditional understanding of how saliva is secreted, and describe how our work has suggested important modifications to this traditional view. We end with a brief description of the most recent data from living animals and discuss how this is now contributing to yet another iteration of model construction and experimental investigation.
Topics: Acinar Cells; Calcium; Humans; Models, Biological; Saliva; Water
PubMed: 33594615
DOI: 10.1007/s11538-020-00841-9 -
Journal of Dental Research Nov 2015Understanding the intrinsic potential for renewal and regeneration within a tissue is critical for the rational design of reparative strategies. Maintenance of the... (Review)
Review
Understanding the intrinsic potential for renewal and regeneration within a tissue is critical for the rational design of reparative strategies. Maintenance of the salivary glands is widely thought to depend on the differentiation of stem cells. However, there is also new evidence that homeostasis of the salivary glands, like that of the liver and pancreas, relies on self-renewal of differentiated cells rather than a stem cell pool. Here, we review the evidence for both modes of turnover and consider the implications for the process of regeneration. We propose that the view of salivary glands as postmitotic and dependent on stem cells for renewal be revised to reflect the proliferative activity of acinar cells and their role in salivary gland homeostasis.
Topics: Acinar Cells; Animals; Cell Proliferation; Homeostasis; Humans; Regeneration; Salivary Glands; Stem Cells
PubMed: 26285812
DOI: 10.1177/0022034515599770 -
Developmental Cell Nov 2016Acinar cells make up the majority of all cells in the pancreas, yet the source of new acinar cells during homeostasis remains unknown. Using multicolor lineage-tracing...
Acinar cells make up the majority of all cells in the pancreas, yet the source of new acinar cells during homeostasis remains unknown. Using multicolor lineage-tracing and organoid-formation assays, we identified the presence of a progenitor-like acinar cell subpopulation. These cells have long-term self-renewal capacity, albeit in a unipotent fashion. We further demonstrate that binuclear acinar cells are terminally differentiated acinar cells. Transcriptome analysis of single acinar cells revealed the existence of a minor population of cells expressing progenitor markers. Interestingly, a gain of the identified markers accompanied by a transient gain of proliferation was observed following chemically induced pancreatitis. Altogether, our study identifies a functionally and molecularly distinct acinar subpopulation and thus transforms our understanding of the acinar cell compartment as a pool of equipotent secretory cells.
Topics: Acinar Cells; Aging; Animals; Cell Lineage; Cell Nucleus; Cell Proliferation; Clone Cells; Humans; Mice, Inbred C57BL; Organoids; Pancreas; Single-Cell Analysis; Stathmin
PubMed: 27923766
DOI: 10.1016/j.devcel.2016.10.002 -
Cell Death & Disease Jun 2020The inflammatory response in acute pancreatitis (AP) is associated with acinar-to-dendritic cell transition. The CD4 T-cell-mediated adaptive immune response is...
The inflammatory response in acute pancreatitis (AP) is associated with acinar-to-dendritic cell transition. The CD4 T-cell-mediated adaptive immune response is necessary for pancreatic inflammatory damage. However, the effect of acinar-to-dendritic cell transition on the CD4 T-cell response and the regulatory mechanism remain undefined. A mouse animal model of AP was established by repeated intraperitoneal injection of CAE. The mTOR inhibitor rapamycin was administered before AP induction. Primary acinar cells were isolated and co-incubated with subsets of differentiated CD4 T cells. The expression of DC-SIGN was also assessed in pancreatic tissues from human AP patients. We found acinar cells expressed DC-SIGN and displayed the phenotype of dendritic cells (DCs), which promoted the differentiation of naive CD4 T cells into CD4/IFN-γ Th1 and CD4/IL-17A Th17 cells in pancreatic tissues during AP. DC-SIGN was the target gene of Myc. The mTOR inhibitor rapamycin inhibited AP-induced DC-SIGN expression, CD4 Th1/Th17 cell differentiation and the pro-inflammatory response via Myc. Acinar cells expressed DC-SIGN in pancreatic tissues of human patients with AP. In conclusion, acinar-to-dendritic cell transition is implicated in the CD4 T-cell immune response via mTOR-Myc-DC-SIGN axis, which might be an effective target for the prevention of local pancreatic inflammation in AP.
Topics: Acinar Cells; Animals; CD4-Positive T-Lymphocytes; Cell Adhesion Molecules; Cell Communication; Cell Differentiation; Cytokines; Dendritic Cells; Humans; Inflammation; Lectins, C-Type; Mice, Inbred C57BL; Pancreas; Pancreatitis; Proto-Oncogene Proteins c-myc; Receptors, Cell Surface; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Th1 Cells; Th17 Cells; Up-Regulation
PubMed: 32488108
DOI: 10.1038/s41419-020-2517-x -
Biomolecules Oct 2022The cytosolic concentration of free calcium ions ([Ca2+]) is an important intracellular messenger in most cell types, and the spatial distribution of [Ca2+] is often...
The cytosolic concentration of free calcium ions ([Ca2+]) is an important intracellular messenger in most cell types, and the spatial distribution of [Ca2+] is often critical. In a salivary gland acinar cell, a polarised epithelial cell, whose principal function is to transport water and thus secrete saliva, [Ca2+] controls the secretion of primary saliva, but increases in [Ca2+] are localised to the apical regions of the cell. Hence, any quantitative explanation of how [Ca2+] controls saliva secretion must take into careful account the spatial distribution of the various Ca2+ sources, Ca2+ sinks, and Ca2+-sensitive ion channels. Based on optical slices, we have previously constructed anatomically accurate three-dimensional models of seven salivary gland acinar cells, and thus shown that a model in which Ca2+ responses are confined to the apical regions of the cell is sufficient to provide a quantitative and predictive explanation of primary saliva secretion. However, reconstruction of such anatomically accurate cells is extremely time consuming and inefficient. Here, we present an alternative, mostly automated method of constructing three-dimensional cells that are approximately anatomically accurate and show that the new construction preserves the quantitative accuracy of the model.
Topics: Calcium; Acinar Cells; Ion Channels; Ions; Water
PubMed: 36291663
DOI: 10.3390/biom12101455 -
International Journal of Molecular... Apr 2019Mitochondrial dysfunction is a core feature of acute pancreatitis, a severe disease in which oxidative stress is elevated. Mitochondrial targeting of antioxidants is a...
Mitochondrial dysfunction is a core feature of acute pancreatitis, a severe disease in which oxidative stress is elevated. Mitochondrial targeting of antioxidants is a potential therapeutic strategy for this and other diseases, although thus far mixed results have been reported. We investigated the effects of mitochondrial targeting with the antioxidant MitoQ on pancreatic acinar cell bioenergetics, adenosine triphosphate (ATP) production and cell fate, in comparison with the non-antioxidant control decyltriphenylphosphonium bromide (DecylTPP) and general antioxidant -acetylcysteine (NAC). MitoQ (µM range) and NAC (mM range) caused sustained elevations of basal respiration and the inhibition of spare respiratory capacity, which was attributable to an antioxidant action since these effects were minimal with DecylTPP. Although MitoQ but not DecylTPP decreased cellular NADH levels, mitochondrial ATP turnover capacity and cellular ATP concentrations were markedly reduced by both MitoQ and DecylTPP, indicating a non-specific effect of mitochondrial targeting. All three compounds were associated with a compensatory elevation of glycolysis and concentration-dependent increases in acinar cell apoptosis and necrosis. These data suggest that reactive oxygen species (ROS) contribute a significant negative feedback control of basal cellular metabolism. Mitochondrial targeting using positively charged molecules that insert into the inner mitochondrial member appears to be deleterious in pancreatic acinar cells, as does an antioxidant strategy for the treatment of acute pancreatitis.
Topics: Acetylcysteine; Acinar Cells; Adenosine Triphosphate; Animals; Antioxidants; Cell Death; Cell Lineage; Cell Survival; Energy Metabolism; Flavin-Adenine Dinucleotide; Mice, Inbred C57BL; Mitochondria; NAD; Onium Compounds; Organophosphorus Compounds; Oxidation-Reduction; Pancreas; Ubiquinone
PubMed: 30959771
DOI: 10.3390/ijms20071700