Single-cell transcriptomic resolution of human pancreatic islets reveals cellular states and intercellular interactions associated with type 1 diabetes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148073 | GEO | 2021/04/03
REPOSITORIES: GEO
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Project description:Dysbiosis of the gut microbiota has been linked to disease pathogenesis in type 1 diabetes (T1D), yet the functional consequences to the host of this dysbiosis is unknown. Here, we have performed a metaproteomic analysis of 103 stool samples from subjects that either had recent-onset T1D, were high-risk autoantibody positive or low-risk autoantibody negative relatives of individuals with beta cell autoimmunity or healthy individuals to identify signatures in host and microbial proteins associated with disease risk. Multivariate modelling analysis demonstrated that both human host proteins and microbial derived proteins could be used to differentiate new-onset and seropositive individuals from low-risk and healthy controls. Significant alterations were identified between subjects with T1D or islet autoimmunity versus autoantibody negative and control subjects in the prevalence of individual host proteins associated with exocrine pancreas function, inflammation and mucosal function. Data integrationIntegrative analysis combining the metaproteomic data with bacterial abundance showed that taxa that were depleted in new-onset T1D patients were positively associated with host proteins involved in maintaining function of the mucous barrier, microvilli adhesion and exocrine pancreas. These data support the notion that T1D patients have increased intestinal inflammation and decreased barrier function. They also confirmed that pancreatic exocrine dysfunction occurs in new-onset T1D patients and show for the first time that this dysfunction is present in high-risk individuals prior to disease onset. Our data has identified a unique T1D-associated signature in stool that may be useful as a means to monitor disease progression or response to therapies aimed at restoring a healthy microbiota.
2018-11-07 | PXD008870 | Pride
Project description:Single-cell transcriptomic resolution of human pancreatic islets reveals cellular states and intercellular interactions associated with type 1 diabetes
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Project description:The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we analyzed larger RO T1D, HC, and healthy T1D sibling cohorts. In addition, we examined T1D progression by looking at longitudinal samples. UPN727 cells were stimulated with Auto-antibody-negative (AA-) High HLA Risk Siblings plasma (n=30), Auto-antibody-negative (AA-) Low HLA Risk Siblings plasma (n=42), Recent onset T1DM plasma cultured with IL1RA (n=42), or longitudinal series plasma on T1DM progressor (n=27 chips, 5 series), on auto-antibody-positive (AA+) High HLA Risk Siblings (n=54 chips, 9 series), on auto-antibody-negative (AA-) High HLA Risk Siblings (n=60 chips, 12 series), on auto-antibody-negative (AA-) Low HLA Risk Siblings (n=31 chips, 6 series). Gene expression analysis was perfromed in order to evaluate the transcriptional signature associated with T1D.
2014-05-13 | E-GEOD-52724 | biostudies-arrayexpress
Project description:Genomic changes in the pancreas across stages of type 1 diabetes (T1D) progression are poorly understood. In this study, we performed single nucleus RNA-seq and ATAC-seq in whole pancreas samples obtained from non-diabetic, autoantibody-positive, and T1D organ donors. Genomic profiles from 480,154 cells were mapped to 18 pancreatic cell types and sub-types, and we identified altered abundance of beta, delta, immune, and exocrine sub-type cells in T1D progression. Beta, delta, acinar, stellate, and other cell types had marked gene expression changes in both autoantibody-positive and recent-onset T1D together with key epigenomic drivers of altered cell type-specific gene activity. Combining cell type-specific changes in T1D progression with genetic association data revealed cellular pathways of T1D risk, including antigen presentation and interferon signaling in beta cells and metabolism in acinar cells. We identified changes in predicted cell signaling in the pancreas in T1D, including immune-beta signals associated with increased disease risk. Finally, we observed several ligands with altered signaling to beta cells in T1D that had protective effects on beta cell regulation in vitro. These results revealed genomic changes in the pancreas driving T1D risk and progression, observations that form the basis for future therapeutic targets for disease intervention.
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Project description:Genomic changes in the pancreas across stages of type 1 diabetes (T1D) progression are poorly understood. In this study, we performed single nucleus RNA-seq and ATAC-seq in whole pancreas samples obtained from non-diabetic, autoantibody-positive, and T1D organ donors. Genomic profiles from 480,154 cells were mapped to 18 pancreatic cell types and sub-types, and we identified altered abundance of beta, delta, immune, and exocrine sub-type cells in T1D progression. Beta, delta, acinar, stellate, and other cell types had marked gene expression changes in both autoantibody-positive and recent-onset T1D together with key epigenomic drivers of altered cell type-specific gene activity. Combining cell type-specific changes in T1D progression with genetic association data revealed cellular pathways of T1D risk, including antigen presentation and interferon signaling in beta cells and metabolism in acinar cells. We identified changes in predicted cell signaling in the pancreas in T1D, including immune-beta signals associated with increased disease risk. Finally, we observed several ligands with altered signaling to beta cells in T1D that had protective effects on beta cell regulation in vitro. These results revealed genomic changes in the pancreas driving T1D risk and progression, observations that form the basis for future therapeutic targets for disease intervention.
2025-09-17 | GSE273598 | GEO
Project description:Genomic changes in the pancreas across stages of type 1 diabetes (T1D) progression are poorly understood. In this study, we performed single nucleus RNA-seq and ATAC-seq in whole pancreas samples obtained from non-diabetic, autoantibody-positive, and T1D organ donors. Genomic profiles from 480,154 cells were mapped to 18 pancreatic cell types and sub-types, and we identified altered abundance of beta, delta, immune, and exocrine sub-type cells in T1D progression. Beta, delta, acinar, stellate, and other cell types had marked gene expression changes in both autoantibody-positive and recent-onset T1D together with key epigenomic drivers of altered cell type-specific gene activity. Combining cell type-specific changes in T1D progression with genetic association data revealed cellular pathways of T1D risk, including antigen presentation and interferon signaling in beta cells and metabolism in acinar cells. We identified changes in predicted cell signaling in the pancreas in T1D, including immune-beta signals associated with increased disease risk. Finally, we observed several ligands with altered signaling to beta cells in T1D that had protective effects on beta cell regulation in vitro. These results revealed genomic changes in the pancreas driving T1D risk and progression, observations that form the basis for future therapeutic targets for disease intervention.
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Project description:Genetic risk variants identified in genome-wide association studies (GWAS) of complex disease are primarily non-coding, and translating risk variants into mechanistic insight requires detailed gene regulatory maps in disease-relevant cell types. Here, we combined a GWAS of type 1 diabetes (T1D) in 520,580 samples with candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types defined using single nucleus ATAC-seq (snATAC-seq) of 131,554 nuclei. T1D risk variants were enriched in cCREs active in T cells and additional cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped exocrine-specific cCREs linked to genes with exocrine-specific expression. At the CFTR locus, T1D risk variant rs7795896 mapped in a ductal-specific cCRE which regulated CFTR, and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of large-scale GWAS and single cell epigenomics for understanding the cellular origins of complex disease.
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Project description:Many patients with type 1 diabetes (T1D) have residual beta cells producing small amounts of C-peptide long after disease onset, but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual beta cells and alpha cells persisting in the islet endocrine compartment are largely unknown due to difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant beta cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D alpha cells was markedly reduced and these cells had alterations in transcription factors constituting and alpha and beta cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of alpha-to-beta cell conversion. These results suggest a new explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
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