Human pancreatic islet responses to cytokine treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE254985 | GEO | 2025/05/29
REPOSITORIES: GEO
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Project description:Human pancreatic islet responses to cytokine treatment
| PRJNA1072975 | ENA
Project description:Pancreatic beta-cells are essential for survival, being the only cell type capable of insulin secretion. While they are believed to be vulnerable to damage by inflammatory cytokines such as interleukin-1 beta (IL-1beta) and IFN-gamma, we have recently identified physiological roles for cytokine signaling in rodent beta-cells that include that stimulation of antiviral and antimicrobial gene expression and the inhibition of viral replication. In this study, we examine cytokine-stimulated changes in gene expression in human islets using single-cell RNA sequencing. Surprisingly, the global responses of human islets to cytokine exposure were remarkably blunted compared to our previous observations in the mouse. The small population of human islet cells that were cytokine responsive exhibited increased expression of IL-1beta-stimulated antiviral guanylate binding proteins, just like in the mouse. Most human islet cells were not responsive to cytokines, and this lack of responsiveness was associated with high expression of genes encoding ribosomal proteins. We further correlated the expression levels of RPL5 with stress response genes, and when expressed at high levels, RPL5 is predictive of failure to respond to cytokines in all endocrine cells. Further, we postulate that donor cause of death and isolation methodologies may contribute to stress of the islet preparation. Our findings indicate that induction of stress responses in human islets (associated with isolation and/or cause of death) limit cytokine stimulated gene expression, and we urge caution in the evaluation of studies that have examined cytokine-stimulated gene expression in human islets without evaluation of stress-related gene expression.
2024-04-08 | GSE251730 | GEO
Project description:MHC-I and MHC-II (HLA-DR, HLA-DQ, HLA-DP) bound peptide elution from cytokine treated human pancreatic islets and homologous spleen donors
2024-01-11 | MSV000093843 | MassIVE
Project description:We have used RNA-seq to identify transcripts, including splice variants, expressed in human islets of Langerhans under control condition or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ). A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets. 25/41 of the candidate genes for type 1 diabetes are expressed in islets, and cytokines modified expression of several of these transcripts. 5 human islet of Langerhans preparations examined under 2 conditions (control and cytokine treatment)
2012-03-09 | E-GEOD-35296 | biostudies-arrayexpress
Project description:It is known that the stresses encountered during islet isolation have deleterious effects on beta-cell physiology. The nature of these effects, however, is incompletely known, partly due to the heterogeneity of islet preparations. The objective was to assess the genome-wide effect of islet isolation and in-vitro culture on beta-cell transcriptome. Beta cells identified by their intrinsic autofluorescence, were captured from donor pancreas and isolated islets using Laser Capture Microdissection. Beta cells from donor pancreas serve as the control. Our results indicated induction of a strong inflammatory response induced by islet isolation which continues during in vitro culture manifested by upregulation of several cytokines, chemokines and their receptors. IL-8 was induced by 3.6-fold and 56-fold in fresh and 3-days cultured islets respectively. Concordantly, several pancreatic progenitor cell-specific transcription factors like were upregulated in cultured islets, suggesting progressive transformation of mature beta-cell phenotype toward an immature endocrine cell phenotype. There are three sample types in our experiment; 1) beta-cells captured from the frozen sections of donor pancreas n=8, 2) beta cells extracted from islets frozen immediately after isolation (d0 islets) n=8 and, 3) beta cells extracted from isolated islets frozen after culturing for 3 days (d3 islets) n=5. For the analysis, beta cells from pancreas were considered as the reference point.
2012-02-12 | E-GEOD-29113 | biostudies-arrayexpress
Project description:Endoplasmic reticulum (ER) and inflammatory stress responses are two pathophysiologic factors contributing to islet dysfunction and failure in Type 2 Diabetes (T2D). However, how human islet cells respond to these stressors and whether T2D-associated genetic variants modulate these responses is unknown. To fill this knowledge gap, we profiled transcriptional (RNA-seq) and epigenetic (ATAC-seq) remodeling in human islets exposed to ex vivo ER (thapsigargin) or inflammatory (IL-1β+IFN-γ) stress. 5,427 genes (~32%) were associated with stress responses; most were stressor-specific, including upregulation of genes mediating unfolded protein response (e.g. DDIT3, ATF4) and NFKB signaling (e.g. NFKB1, NFKBIA) in ER stress and cytokine-induced inflammation respectively. Islet single-cell RNA-seq profiling revealed strong but heterogeneous beta cell ER stress responses, including a distinct beta cell subset that highly expressed apoptotic genes. Epigenetic profiling uncovered 14,968 stress-responsive cis-regulatory elements (CREs; ~14%), the majority of which were stressor-specific, and revealed increased accessibility at binding sites of transcription factors that were induced upon stress (e.g. ATF4 for ER stress, IRF8 for cytokine-induced inflammation). Eighty-six stress-responsive CREs overlapped known T2D-associated variants, including 20 residing within CREs that were more accessible upon ER stress. Among these, we linked the rs6917676 T2D risk allele (T) to increased in vivo accessibility of an islet ER stress-responsive CRE and allele-specific beta cell nuclear factor binding in vitro. We showed that MAP3K5, the only ER stress-responsive gene in this locus, promotes beta cell apoptosis. Consistent with its pro-apoptotic and putative diabetogenic roles, MAP3K5 expression inversely correlated with beta cell abundance in human islets and was induced in beta cells from T2D donors. Together, this study provides new genome-wide insights into human islet stress responses and putative mechanisms of T2D genetic variants.
2024-01-15 | GSE251912 | GEO
Project description:Defining the immunological landscape of human tissue is an important area of research, but challenges include the impact of tissue disaggregation on cell phenotypes and the low abundance of immune cells in many tissues. Here, we describe methods to troubleshoot and standardize Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) for studies involving enzymatic digestion of human tissue. We tested epitope susceptibility of 92 antibodies commonly used to differentiate immune lineages and cell states on human peripheral blood mononuclear cells following treatment with an enzymatic digestion cocktail used to isolate islets. We observed CD4, CD8a, CD25, CD27, CD120b, CCR4, CCR6, and PD1 display significant sensitivity to enzymatic treatment, effects that often could not be overcome with alternate antibodies. Comparison of flow cytometry-based CITE-seq antibody titrations and sequencing data supports that for the majority of antibodies, flow cytometry accurately predicts optimal antibody concentrations for CITE-seq. Comparison by CITE-seq of immune cells in enzymatically digested islet tissue and donor- matched spleen not treated with enzymes revealed little digestion-induced epitope cleavage, suggesting increased sensitivity of CITEseq and/or that the islet structure may protect resident immune cells from enzymes. Within islets, CITEseq identified immune cells difficult to identify by transcriptional signatures alone, such as distinct tissue-resident T cell subsets, mast cells, and innate lymphoid cells (ILCs). Collectively this study identifies strategies for the rational design and testing of CITE-seq antibodies for single-cell studies of immune cells within islets and other tissues.
2023-02-12 | GSE224767 | GEO
Project description:We anticipated that the identification of cis-regulatory regions active in pancreatic islets would help increase our understanding of islet biology and the pathology of diabetes. Towards this end we used histone H3 lysine 4 monomethylation-based nucleosome predictions genome-wide, in conjunction with binding data for PDX1, FOXA2, MAFA, and NEUROD1, to identify 3,654 putative enhancers that are H3K4me1-enriched uniquely in islets as compared to 14 other tissue or cell-types. We show that these islet-specific enhancers are associated with genes with significantly higher islet specificity than genes associated with non-specific enhancers. Further, islet-specific enhancers were not enriched for typical active or repressive histone methylations in embryonic stem cells and liver, suggesting they are formed by de novo histone methylation during pancreas development. We also identify a subset of enhancers bivalently marked by both H3K4me1 and H3K27me3 in adult pancreatic islets. Further, we show that islet-specific enhancers triple- or quadruple- bound by PDX1, MAFA, NEUROD1 and/or FOXA2 are associated with genes with particularly high islet-specificity, and that these loci are enriched in regions with functional activity in islet cell types. Finally, we demonstrate that cytokines reduce H3K4me1 enrichment levels at selected triple- or quadruple-bound islet-specific enhancers, suggesting that epigenetic changes may contribute to cytokine-induced b-cell dysfunction. In conjunction with data from Hoffman et al Genome Research 2010, an analysis of histone modifications and transcription factor binding sites to identify enhancer regions
2011-06-30 | E-GEOD-30298 | 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. Transcriptional dissection of human pancreatic islets of one donor using single-cell RNA-seq
2016-01-05 | E-GEOD-73727 | biostudies-arrayexpress
Project description:Study to map diabetes-related traits in the Diversity Outbred (DO) mouse cohort. The DO is an outbred mouse population derived from 8 inbred mouse strains, including 3 wild-derived strains. The DO captures a broad range of genetic variation comparable to that found in human populations (SVENSON et al. 2012), and presents a similarly broad range of individual susceptibility to T2D. We metabolically challenged 500 DO mice with a high-fat/high-sucrose diet, measured a host of diabetes-related physiological phenotypes (e.g., plasma glucose and insulin), and isolated their pancreatic islets for functional and molecular characterization. We performed RNA-seq to determine the genetic architecture of gene expression in islets
2024-05-24 | GSE267728 | GEO