Effect of beta cell ablation on pancreatic ductal cells in adult zebrafish
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE212124 | GEO | 2024/09/01
REPOSITORIES: GEO
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Project description:Effect of beta cell ablation on pancreatic ductal cells in adult zebrafish
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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:Pancreatic ductal adenocarcinoma
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Project description:Pathways that stimulate β-cell regeneration remain of great clinical interest, yet effective therapeutic avenues that promote survival or reconstitution of β-cell mass remain elusive. Utilizing a mouse model with inducible β-cell apoptosis followed by adiponectin-mediated regeneration, we aimed to identify key molecules boosting β-cell viability. Within the regenerating pancreatic islets, we examined changes within the transcriptome, and observed an extensive upregulation of genes encoding proteins involved in lipid transport and metabolism. The most prominent targets were further confirmed by quantitative PCR and immunofluorescence. Among the upstream regulators predicted by pathway analysis of the transcriptome, we detected enhanced levels of two key transcription factors, HNF4α and PPARα. Enhanced leptin levels in circulation may also contribute to the anti-lipotoxic program in islets. In summary, our data suggest that improving local lipid metabolism as an important anti-lipotoxic phenomenon to boost β-cell regeneration, primarily mediated by adiponectin’s action on the β-cells directly as well as on the adipocyte. RNA profiles of pancreatic islets isolated from PANIC-ATTAT mice crossed with adiponectin wild-type (P-Adn+/+) or the overexpressing transgene (P-AdnTg/+) at 5 weeks after initial dimerizer administration.
2015-01-09 | E-GEOD-64787 | biostudies-arrayexpress
Project description:The adult pancreas is capable of limited regeneration after injury, but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into β-cells. The induced β-cells resemble islet β-cells in morphology and histology, express genes essential for β-cell function, and release insulin upon glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type. We used microarray to compare adult mouse fbw7 knock out ductal cells with bonafide beta cells In order to isolate fbw7 ko, fbw7 wt ductal cells and beta cells we used adult mice with the following genotypes: MIP-GFP (beta cells are constitutively labelled with GFP), Ck19-CreERT; R26-LSL-YFP; Fbw7 +/+ (ductal cells are labelled with YFP upon tamoxifen injection) and Ck19-CreERT; R26-LSL-YFP; Fbw7 F/F mice (ductal cells are labelled with YFP upon tamoxifen injection). 30000 GFP+ cells were isolated by FACS-sorting. RNA was extracted and amplified using NuGEN kit.
2014-08-07 | E-GEOD-58969 | biostudies-arrayexpress
Project description:To determine the molecular basis of gene regulation in pancreatic ductal epithelial cells, we developed methods for the isolation of this cell population during mouse development and normal adult homeostasis, as well as in conditions with ductal features (acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC)). Our technique utilizes the specificity of Dolichos biflorus Agglutinin (DBA) lectin marking the entire normal ductal tree, including terminal intercalated ducts (putative sites of stem or progenitor cells) and ductal structures in ADM and PanIN. We used ferromagnetic-labeled DBA lectin to isolate ductal structures. Ductal cells were isolated under the following conditions: (1) Embryonic Development in wild type mice: E14.5, E15.5, E16.5, and postnatal day 1 (P1); (2) Injury and regeneration (pancreatitis) 0, 1, 3, 5 days following cerulein-induced acute pancreatitis. Cerulein is a cholecystokinin analog which produces a self-limited pancreatitis with injury and subsequent regeneration and repair, completed five days after insult; and (3) Pdx1-Cre;LSL-KrasG12D/+ mice aged 10 and 20 weeks that harbor PanIN lesions and a subset develop PDAC. Ductal/PanIN cells were isolated from these mice and appropriate control mice (Pdx1-Cre;Kras+/+).
2015-09-30 | GSE40895 | GEO
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
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.
2023-06-05 | GSE233785 | GEO