Effect of beta cell ablation on pancreatic ductal cells in adult zebrafish
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE212124 | GEO | 2024/09/01
REPOSITORIES: GEO
Similar Datasets
Project description:Effect of beta cell ablation on pancreatic ductal cells in adult zebrafish
| PRJNA874056 | ENA
Project description:Introduction/Objective: Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of insulin-producing beta cells and has no cure. The role of cell-cell interactions in immune recognition of beta cells remains poorly understood. Beta cells develop adjacent to ductal cells, which undergo changes during T1D progression, suggesting crosstalk between the two cell types. Extracellular vesicles (EVs) mediate intercellular communication through their cargo, but whether human ductal cells secrete EVs that modulate beta cells is unknown. We hypothesize that exposure of human ductal cells to T1D-associated cytokines alters their EV cargo, with consequence in beta cells. Methods: Human exocrine tissues from non-diabetic cadaveric donors were cultured in a 3D suspension to support ductal cell survival. Cells were treated with TNF-α, IL-1β, and IFN-γ or vehicle control for 48 hours and analyzed for proinflammatory-related gene expression and viability by qRT-PCR and Trypan blue exclusion, respectively. EVs from cytokine- and vehicle-treated ductal cells were isolated using size exclusion chromatography and characterized by dot blot, transmission electron microscopy, and nanoparticle tracking. The effects of EVs on EndoC-βH1 human beta cells were assessed with qRT-PCR, RNA-sequencing and flow cytometry, and EV cargo was analyzed by proteomics and transcriptomics. Results: EVs from cytokine-treated ductal cells were internalized by EndoC-βH1 beta cells and, compared to control ductal EVs, increased HLA Class I gene and protein expression in EndoC-βH1 cells, as shown by qRT-PCR, bulk RNA sequencing, and flow cytometry. EV cargo from cytokine-treated versus control ductal cells, was enriched for transcripts associated with inflammatory and antigen-presentation-related pathways, including CXCL9, CXCL10, CXCL11, IDO1, and GBP4. Conclusion: Primary human ductal cells secrete EVs that, under T1D-associated cytokine exposure, alter their cargo and upregulate HLA Class I gene and protein expression in human EndoC-βH1 beta cells. Because HLA Class I is critical for beta cell recognition by autoimmune cells, our results reveal a previously unknown ductal cell communication pathway with implication for modulating beta cells during T1D progression.
2026-01-21 | GSE316823 | GEO
Project description:Pancreatic ductal adenocarcinoma
| PRJNA432344 | ENA
Project description:Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
2024-09-18 | GSE264022 | GEO
Project description:Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
2024-09-18 | GSE264021 | GEO
Project description:Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
2024-09-18 | GSE264019 | GEO
Project description:Peroxisome proliferator-activated receptor beta/delta protects against obesity by reducing dyslipidemia and insulin resistance via effects in various organs, including muscle, adipose tissue, liver, and heart. However, nothing is known about the function of PPAR-beta in pancreas, a prime organ in the control of glucose metabolism. To gain insight into so far hypothetical functions of this PPAR isotype in insulin production, we specifically ablated Ppar-beta in pancreas. The mutated mice developed a chronic hyperinsulinemia, due to an increase in both beta-cell mass and insulin secretion. Gene expression profiling indicated a broad repressive function of PPAR-beta impacting the vesicular compartment, actin cytoskeleton, and metabolism of glucose and fatty acids. Analyses of insulin release from the islets revealed an increased second-phase glucose-stimulated insulin secretion. Higher levels of PKD, PKC-delta and diacyglycerol in mutated animals lead to an enhanced formation of trans-Golgi network (TGN)-to-plasma-membrane transport carriers in concert with F-actin disassembly, which resulted in increased insulin secretion and its associated systemic effects. Taken together, these results provide evidence for PPAR-beta playing a repressive role on beta-cell growth and insulin exocytosis, which shed new light on its anti-obesity action. Pancreas-specific knock-out animals were generated by breeding mice harbouring a floxed Ppar-beta (PPARbetafl/fl) to mice expressing the Cre transgene under the control of the Pdx1 promoter (Pdx1Cre). Islets from 3 different animals from the knock-out group Pdx1Cre;PPARbetafl/fl and the control littermates group PPARbetafl/fl were compared.
2012-08-30 | E-GEOD-16048 | biostudies-arrayexpress
Project description:Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. However, the in vivo role of fibroblasts in structuring the basal ECM network is poorly understood. To examine the effects of fibroblast loss on the microenvironment in the adult murine heart, we generated mice with reduced fibroblast numbers and evaluated the tissue microenvironment during homeostasis and after injury. We determined that a 60-80% reduction in fibroblasts numbers did not overtly change the fibrillar collagen network but did alter the distribution and abundance of type VI collagen, a microfibrillar collagen that forms an open network with the basement membrane. In fibroblast ablated mice, myocardial infarction did not result in ventricular wall rupture, and heart function was more effectively preserved during angiotensin II/phenylephrine (AngII/PE) induced fibrosis. Analysis of cardiomyocyte contractility demonstrated weaker contractions and slower calcium release and reuptake in uninjured and AngII/PE infused fibroblast ablated animals. Moreover, fibroblast ablated hearts have a similar gene expression prolife to hearts with exercise-induced and physiological hypertrophy after AngII/PE infusion. These results suggest that hearts are resilient to a significant degree of fibroblast loss and that fibroblasts can directly impact cardiomyocyte function. Furthermore, a reduction in fibroblasts may have cardioprotective effects heart after injury suggesting that manipulation of the number of fibroblasts may have therapeutic value.
2023-03-10 | PXD021739 | Pride
Project description:Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. However, the in vivo role of fibroblasts in structuring the basal ECM network is poorly understood. To examine the effects of fibroblast loss on the microenvironment in the adult murine heart, we generated mice with reduced fibroblast numbers and evaluated the tissue microenvironment during homeostasis and after injury. We determined that a 60-80% reduction in fibroblasts numbers did not overtly change the fibrillar collagen network but did alter the distribution and abundance of type VI collagen, a microfibrillar collagen that forms an open network with the basement membrane. In fibroblast ablated mice, myocardial infarction did not result in ventricular wall rupture, and heart function was more effectively preserved during angiotensin II/phenylephrine (AngII/PE) induced fibrosis. Analysis of cardiomyocyte contractility demonstrated weaker contractions and slower calcium release and reuptake in uninjured and AngII/PE infused fibroblast ablated animals. Moreover, fibroblast ablated hearts have a similar gene expression prolife to hearts with exercise-induced and physiological hypertrophy after AngII/PE infusion. These results suggest that hearts are resilient to a significant degree of fibroblast loss and that fibroblasts can directly impact cardiomyocyte function. Furthermore, a reduction in fibroblasts may have cardioprotective effects heart after injury suggesting that manipulation of the number of fibroblasts may have therapeutic value.
2023-03-10 | PXD021741 | Pride
Project description:Ductal progenitor-like cells are a subpopulation of ductal cells in the adult human pancreas that have the potential to contribute to regenerative medicine. However, the microenvironmental cues that regulate their activation are poorly understood. Here, we establish a 3-dimensional suspension culture system containing six defined soluble factors in which primary human ductal and ductal progenitor-like cells can survive but do not proliferate. Expansion and polarization occur when cells are provided with a low concentration (5% v/v) of Matrigel, a sarcoma cell product enriched in many extracellular matrix (ECM) proteins. Screening of ECM proteins identified that collagen IV is capable of partially recapitulating the effects of Matrigel. Inhibition of integrin α1β1, a major collagen IV receptor, negates collagen IV- and Matrigel-stimulated effects. These results demonstrate that collagen IV is a key ECM protein that stimulates the expansion and polarization of human ductal and ductal progenitor-like cells via integrin α1β1 receptor signaling.
2023-05-31 | GSE233344 | GEO