Single cell RNA sequencing of DHT treated human male Islet cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201256 | GEO | 2023/04/17
REPOSITORIES: GEO
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Project description:The Ppy-gene encodes the pancreatic polypeptide (PP) secreted by PP- or - cells, an endocrine cell type located in the islet periphery. For a detailed characterization of PP cells, we aimed to establish PP cell lines. To this end, we generated Ppy-Cre;Rosa26-CAG-LSL-Large T mice, in which the SV40 large T antigen (TAg) is expressed in Ppy-expressing cells upon Cre-loxP-mediated recombination. Ppy-Cre;Rosa26-CAG-LSL-Large T mice, surprisingly, developed pancreatic ductal adenocarcinoma (PDAC) rapidly by 3 to 4 weeks of age, while mice with insulin2-Cre-mediated activation of TAg developed insulinomas. This suggests that PDACs could arise from the islet/endocrine cells, which is rather unexpected as PDACs are generally believed to originate from the pancreatic acinar or ductal cells. RNA-seq analysis of transformed Ppy-lineage cells in 7-day old islets showed downregulation of endocrine genes, upregulation of exocrine, ductal genes, and upregulation of PDAC-related genes and pathways, respectively. These results suggest that expression of an oncogene in Ppy-lineage cells leads to a fate switch in these endocrine precursors that causes them to adopt a PDAC cell fate. Our findings revealed that Ppy-lineage cells may be one of the origins of PDAC and provide novel insights into the heterogeneity in pathogenesis of pancreatic cancer and its personalized therapy.
2024-06-01 | GSE245435 | GEO
Project description:The cellular identity of pancreatic polypeptide (Ppy)-expressing γ-cells, the rarest pancreatic islet cell-type, remains elusive. Within islets, glucagon and somatostatin, released respectively from α- and δ-cells, modulate the secretion of insulin by β-cells. Dysregulation of insulin production raises blood glucose levels, leading to diabetes onset. Here, we present the genetic signature of human and mouse γ-cells. Using newly developed tools, we identified a set of genes and pathways defining their functional identity. We found that the γ-cell population is heterogeneous, with subsets of cells producing another hormone in addition to Ppy. These bihormonal cells share identity markers typical of the other islet cell-types. In mice, Ppy gene inactivation or conditional γ-cell ablation did not alter glycemia nor body weight. Interestingly, upon β-cell injury induction, γ-cells exhibited gene expression changes and some of them engaged insulin production, like α- and δ-cells. In conclusion, we provide a comprehensive characterization of γ-cells and highlight their plasticity and therapeutic potential.
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Project description:Toolsets available for in-depth analysis of scRNAseq datasets by biologists with little informatics experience is limited. Here we describe an informatics tool (PyMINEr) that fully automates cell type identification, cell type-specific pathway analyses, graph theory-based analysis of gene regulation, and detection of autocrine/paracrine signaling networks in silico. We applied PyMINEr to interrogate human pancreatic islet scRNAseq datasets and discovered several features of co-expression graphs including: concordance of scRNAseq-graph structure with both protein-protein interactions and 3D-genomic architecture; association of high connectivity and low expression genes with cell type-enrichment; and potential for graph-structure to clarify potential etiologies of enigmatic disease-associated variants. We further created a consensus co-expression network and autocrine/paracrine signaling networks within and across islet cell types from 7-datasets. PyMINEr correctly identified changes in BMP/WNT signaling associated with cystic fibrosis pancreatic acinar-cell loss. This proof-of-principle study demonstrates that the PyMINEr framework will be a valuable resource for scRNAseq analyses.
2019-01-11 | GSE116753 | GEO
Project description:We report the single-cell RNA-seq based identification of 6 known human islet cell types (alpha cells, beta cells, delta cells, pp cells, acinar cells and duct cells) based on the expression of known marker genes. We further assess cell type specific gene expression and suggest novel marker genes for several cell types. Transcriptional dissection of human pancreatic islets of one donor using single-cell RNA-seq
2016-01-05 | E-GEOD-73727 | biostudies-arrayexpress
Project description:We report the single-cell RNA-seq based identification of 6 known human islet cell types (alpha cells, beta cells, delta cells, pp cells, acinar cells and duct cells) based on the expression of known marker genes. We further assess cell type specific gene expression and suggest novel marker genes for several cell types.
2016-01-05 | GSE73727 | GEO
Project description:LCM-coupled nanoPOTS proteomics using FAIMS of intra-islet microstructures. 5 acinar samples, 5 whole islets, 5 islet interface vasculature pools, 5 islet inner microvasculature pools, 3 islets after microsvasculature removed.
2022-01-25 | MSV000088730 | MassIVE
Project description:Blood glucose levels are tightly controlled by the coordinated action of at least five cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 diabetes (T2D). Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet dysfunction, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single cell transcriptomes for 617 islet cells after profiling ~1000 cells from non-diabetic (ND) and T2D human organ donors. Analyses of non-diabetic single cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. Grant ID: Award No. W81XWH-16-1-0130 Grant title: Peer Reviewed Medical Research Program Funding Source: Assistant Secretary of Defense for Health Affairs Affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT Name: Michael Stitzel
2016-11-09 | GSE86468 | GEO
Project description:Blood glucose levels are tightly controlled by the coordinated action of at least five cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 diabetes (T2D). Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet dysfunction, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single cell transcriptomes for 617 islet cells after profiling ~1000 cells from non-diabetic (ND) and T2D human organ donors. Analyses of non-diabetic single cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. Grant ID: Award No. W81XWH-16-1-0130 Grant title: Peer Reviewed Medical Research Program Funding Source: Assistant Secretary of Defense for Health Affairs Affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT Name: Michael Stitzel
2016-11-09 | GSE86469 | GEO
Project description:Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific subtypes of cells, closely related cells with distinct properties. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprogram pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells at the onset of reprogramming in addition to promoting δ-specification. Mafa and Pdx1 suppress δ-specification in α- and β-cell formation. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. induced beta cells samples at day 10 collected for the microarray
2013-11-20 | E-GEOD-52522 | biostudies-arrayexpress
Project description:Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific subtypes of cells, closely related cells with distinct properties. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprogram pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells at the onset of reprogramming in addition to promoting δ-specification. Mafa and Pdx1 suppress δ-specification in α- and β-cell formation. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo.
2013-11-20 | GSE52522 | GEO