scholarly journals SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells

2020 ◽  
Author(s):  
Katie C. Coate ◽  
Jeeyeon Cha ◽  
Shristi Shrestha ◽  
Wenliang Wang ◽  
Luciana Mateus Gonçalves ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Endocrine Cells ◽  
Islet Cells ◽  
Cell Entry ◽  
Pancreatic Ducts ◽  
Human Pancreas ◽  
Β Cells ◽  
Ductal Cells ◽  
Putative Receptor ◽  
New Onset

Summary/AbstractReports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.

Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion

2010 ◽  
Vol 299 (4) ◽  
pp. E647-E656 ◽  
Author(s):  
Elise G. Lavoie ◽  
Michel Fausther ◽  
Gilles Kauffenstein ◽  
Filip Kukulski ◽  
Beat M. Künzli ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Cells ◽  
Islet Cells ◽  
Receptor Activation ◽  
Extracellular Nucleotides ◽  
Local Concentration ◽  
Human Pancreas ◽  
Β Cells ◽  
Potential Implication ◽  
Langerhans Islets

Extracellular nucleotides and adenosine regulate endocrine pancreatic functions such as insulin secretion by Langerhans islet β-cells via the activation of specific P2 and P1 receptors. Membrane-bound ectonucleotidases regulate the local concentration of these ligands and consequently control the activation of their receptors. The objective of this study was to identify and localize the major ectonucleotidases, namely NTPDases and ecto-5′-nucleotidase, present in the endocrine pancreas. In addition, the potential implication of ecto-ATPase activity on insulin secretion was investigated in the rat β-cell line INS-1 (832/13). The localization of ectonucleotidase activity and protein was carried out in situ by enzyme histochemistry and immunolocalization in mouse, rat, and human pancreas sections. NTPDase1 was localized in all blood vessels and acini, and NTPDase2 was localized in capillaries of Langerhans islets and in peripheral conjunctive tissue, whereas NTPDase3 was detected in all Langerhans islet cell types. Interestingly, among the mammalian species tested, ecto-5′-nucleotidase was present only in rat Langerhans islet cells, where it was coexpressed with NTPDase3. Notably, the inhibition of NTPDase3 activity by BG0136 and NF279 facilitated insulin release from INS-1 (832/13) cells under conditions of low glycemia, probably by affecting P2 receptor activation. NTPDase3 activity also regulated the inhibitory effect of exogenous ATP in the presence of a high glucose concentration most likely by controlling adenosine production. In conclusion, all pancreatic endocrine cells express NTPDase3 that was shown to modulate insulin secretion in rat INS-1 (832/13) β-cells. Ecto-5′-nucleotidase is expressed in rat Langerhans islet cells but absent in human and mouse endocrine cells.

scholarly journals Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

2020 ◽  
Vol 117 (20) ◽  
pp. 10876-10887 ◽  
Author(s):  
Mirza Muhammad Fahd Qadir ◽  
Silvia Álvarez-Cubela ◽  
Dagmar Klein ◽  
Jasmijn van Dijk ◽  
Rocío Muñiz-Anquela ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ducts ◽  
Human Pancreas ◽  
Immunodeficient Mice ◽  
Ductal Cells ◽  
Surrogate Surface ◽  
Morphogenetic Protein ◽  
Resolution Analysis ◽  
Cell Niche ◽  
Acinar Tissue

We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII− cells) differentiate into all pancreatic lineages, including functional β-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII− progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

Carbamoylcholine regulation of polyphosphoinositide synthesis and hydrolysis in cultured, dispersed, digitonin-permeabilized mouse pancreatic islet cells

1997 ◽  
Vol 136 (5) ◽  
pp. 539-545 ◽  
Author(s):  
Andrew M Kardasz ◽  
Peter Thams ◽  
Kirsten Capito ◽  
Carl J Hedeskov
Keyword(s):  
Pancreatic Islet ◽  
Kinase Activity ◽  
Inositol Phosphates ◽  
Islet Cells ◽  
Pancreatic Islet Cells ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Mouse Pancreatic Islet ◽  
Phosphatidylinositol 4 ◽  
Stimulation Of

Abstract Continuing formation of inositol phosphates during stimulation of pancreatic β-cells by hormones and neurotransmitters requires the continued synthesis of the polyphosphoinositides phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5 bisphosphate (PIP2) from phosphatidylinositol (PI). In the present study we have investigated how this pathway and the activity of phosphoinositide-specific phospholipase C (PI-PLC) are regulated by carbamoylcholine (CCh), Ca2+, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), GTPγS and NaF in 44-h [3H]inositol-labelled, dispersed and digitonin-permeabilized mouse pancreatic islet cells. CCh stimulated not only PI-PLC (G-protein-mediated) but also, by an as yet unknown mechanism, significantly enhanced PI 4-kinase activity, estimated as the PIP:PI ratio, by 100%, and further increased the flux from PI to PIP and PIP2. GTPγS and NaF mimicked the effects of CCh on PI-PLC but had no effect on the levels of PIP and PIP2. TPA raised the PIP:PI ratio by 75%. In addition TPA counteracted the CCh stimulation of PI-PLC. There was no effect of 10−6 mol/l Ca2+ on the levels of PIP and PIP2. Experiments with quinacrine and adenosine confirmed that PI-PLC and PI 4-kinase could be regulated independently of each other. In conclusion, these data point to differential regulation of polyphosphoinositide synthesis and breakdown. European Journal of Endocrinology 136 539–545

scholarly journals Functional and Morphological Characteristics of Pancreatic Islet Lesions Induced by Quinolone Antimicrobial Agent Gatifloxacin in Rats

2018 ◽  
Vol 47 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Koichi Yabe ◽  
Yuka Yamamoto ◽  
Takami Suzuki ◽  
Sanae Takada ◽  
Kazuhiko Mori
Keyword(s):  
Pancreatic Islet ◽  
Islet Cells ◽  
Serum Glucose ◽  
Male Rats ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Intravenous Glucose ◽  
Insulin Synthesis ◽  
Cytoplasmic Vacuoles ◽  
Impaired Insulin

We characterized pancreatic islet lesions induced by several quinolones using functional and morphological examinations of the pancreatic islets in male rats orally administered gatifloxacin, lomefloxacin, or levofloxacin at 300 mg/kg for 14 consecutive days. Consequently, in contrast to lomefloxacin or levofloxacin, gatifloxacin increased serum glucose and glycosylated albumin on day 14 and elevated serum glucose tended to decrease insulin in the intravenous glucose tolerance test. Microscopically, only gatifloxacin induced cytoplasmic vacuoles containing eosinophilic homogenous contents in islet cells. Immunohistochemical examination revealed that vacuolated islet cells were positively stained for insulin, demonstrating they were pancreatic β cells. Electron microscopy showed that the cytoplasmic vacuoles represented dilated cisterna of the rough endoplasmic reticulum filled with electron-lucent materials in pancreatic β cells. Moreover, insulin secretory granules were drastically decreased in vacuolated islet cells, suggesting impaired insulin synthesis and/or transport. This gatifloxacin-induced pancreatic toxicity in rats was considered to be associated with high pancreatic drug distribution. These results demonstrated that gatifloxacin provoked functional and morphological pancreatic β cell alteration associated with impaired insulin synthesis and/or transport, leading to hyperglycemia.

scholarly journals The Cells of the Islets of Langerhans

2018 ◽  
Vol 7 (3) ◽  
pp. 54 ◽  
Author(s):  
Gabriela Da Silva Xavier
Keyword(s):  
Islets Of Langerhans ◽  
Islet Cell ◽  
Islet Cells ◽  
Cell Mass ◽  
Current Data ◽  
Treatment Modalities ◽  
Human Pancreas ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.

scholarly journals Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

2021 ◽  
Author(s):  
D. Sarnobat ◽  
R. C. Moffett ◽  
P. R. Flatt ◽  
A. I. Tarasov
Keyword(s):  
Pancreatic Islet ◽  
Cell Apoptosis ◽  
Islet Cells ◽  
Early Stage ◽  
Proliferative Potential ◽  
Low Doses ◽  
Β Cells ◽  
Β Cell ◽  
Oral Hypoglycaemic Agents ◽  
The Impact

Abstract Aims Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets. Methods Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence. Results The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed. Conclusions Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion.

scholarly journals SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature

2020 ◽  
Author(s):  
Daniela Fignani ◽  
Giada Licata ◽  
Noemi Brusco ◽  
Laura Nigi ◽  
Giuseppina E. Grieco ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Human Pancreas ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Β Cells ◽  
Β Cell ◽  
Human Pancreatic Islets ◽  
Ductal Cells ◽  
Angiotensin I Converting Enzyme

AbstractIncreasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2), is a necessary step for SARS-CoV-2 infection permissiveness. In the light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyse ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies.Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing β-cells. ACE2 is also is highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. By using different ACE2 antibodies we showed that a recently described short-ACE2 isoform is also prevalently expressed in human β-cells.Finally, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, but not palmitate, increases ACE2 expression in the β-cell line EndoC-βH1 and in primary human pancreatic islets.Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes through putative infection of pancreatic microvasculature and/or ductal cells and/or through direct β-cell virus tropism.

scholarly journals Pancreatic Duct Cells Isolated From Canines Differentiate Into Beta-Like Pancreatic Islet Cells

2022 ◽  
Vol 8 ◽  
Author(s):  
Yuhua Gao ◽  
Weijun Guan ◽  
Chunyu Bai
Keyword(s):  
Pancreatic Islet ◽  
Pancreatic Beta Cells ◽  
Islet Cells ◽  
Pancreatic Islet Cells ◽  
Cell Therapies ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Granules ◽  
Glucose Stimulated Insulin Secretion

In this study, we isolated and cultured pancreatic ductal cells from canines and revealed the possibility for using them to differentiate into functional pancreatic beta cells in vitro. Passaged pancreatic ductal cells were induced to differentiate into beta-like pancreatic islet cells using a mixture of induced factors. Differentiated pancreatic ductal cells were analyzed based on intracellular insulin granules using transmission electron microscopy, the expression of insulin and glucagon using immunofluorescence, and glucose-stimulated insulin secretion using ELISA. Our data revealed that differentiated pancreatic ductal cells not only expressed insulin and glucagon but also synthesized insulin granules and secreted insulin at different glucose concentrations. Our study might assist in the development of effective cell therapies for the treatment of type 1 diabetes mellitus in dogs.

scholarly journals Expression and Function of αvβ3 and αvβ5 Integrins in the Developing Pancreas

2000 ◽  
Vol 150 (6) ◽  
pp. 1445-1460 ◽  
Author(s):  
Vincenzo Cirulli ◽  
Gillian M. Beattie ◽  
George Klier ◽  
Mark Ellisman ◽  
Camillo Ricordi ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Critical Role ◽  
Pancreatic Ducts ◽  
Cellular Interactions ◽  
Ductal Epithelium ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Tissue Organization ◽  
And Function

Cell–cell and cell–matrix interactions play a critical role in tissue morphogenesis and in homeostasis of adult tissues. The integrin family of adhesion receptors regulates cellular interactions with the extracellular matrix, which provides three-dimensional information for tissue organization. It is currently thought that pancreatic islet cells develop from undifferentiated progenitors residing within the ductal epithelium of the fetal pancreas. This process involves cell budding from the duct, migration into the surrounding mesenchyme, differentiation, and clustering into the highly organized islet of Langerhans. Here we report that αvβ3 and αvβ5, two integrins known to coordinate epithelial cell adhesion and movement, are expressed in pancreatic ductal cells and clusters of undifferentiated cells emerging from the ductal epithelium. We show that expression and function of αvβ3 and αvβ5 integrins are developmentally regulated during pancreatic islet ontogeny, and mediate adhesion and migration of putative endocrine progenitor cells both in vitro and in vivo in a model of pancreatic islet development. Moreover, we demonstrate the expression of fibronectin and collagen IV in the basal membrane of pancreatic ducts and of cell clusters budding from the ductal epithelium. Conversely, expression of vitronectin marks a population of epithelial cells adjacent to, or emerging from, pancreatic ducts. Thus, these data provide the first evidence for the contribution of integrins αvβ3 and αvβ5 and their ligands to morphogenetic events in the human endocrine pancreas.

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