Human pancreatic beta cell transcriptomes from donors with and without T1D
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PROVIDER: PRJNA1074280 | ENA |
REPOSITORIES: ENA
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Project description:We compared the transcriptome of bulk sorted T1D donor beta cells to those from non-diabetic donors.
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Project description:Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing pancreatic beta cells, leading to life-long dependence on exogenous insulin. Profiling immune cells that infiltrate islets would be invaluable to understanding how beta cell destruction occurs. However, human pancreatic samples demonstrating active infiltration and beta cell destruction are rare. Alternatively, peri-pancreatic lymph nodes (pLNs) or other secondary lymphoid organs may harbor immune cells which participate in memory responses that drive T1D autoimmunity. To study the immune response throughout T1D onset and disease, lymphocytes from pLNs, mesenteric lymph nodes (mesLNs), and the spleen were collected from human T1D, auto-antibody positive (AAb+), and normal donors (NDs) enrolled in the Human Pancreas Analysis Program (HPAP). Tissue immune cell identity, phenotype, and transcriptional status was analyzed using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq). Lymphocytes from 17 pLN, 9 mesLN, and 15 spleen samples spanning 7 ND, 5 AAb+, and 7 T1D donors were thawed and processed through the CITEseq pipeline. 5 donors per disease group had a paired pLN and spleen sample, with 3 of the 5 donors having a paired mesLN sample, allowing for cross-tissue immune status comparison spanning multiple stages of disease onset. The dataset provides one of the first and largest CITEseq datasets on human AAb+ and T1D samples publicly available.
2023-01-03 | GSE221787 | GEO
Project description:Emerging evidence points towards an intricate relationship between the pandemic coronavirus disease 2019 (COVID-19) and diabetes. While diabetes is associated with an increased risk of severe COVID-19, new-onset type 1 diabetes (T1D) has been observed in COVID-19 patients, convoluting diabetes as both a risk factor and consequence of COVID-19. Understanding the mechanistic relationship between COVID-19 and T1D is an urgent and critical public health challenge. One pressing question is whether insulin-producing pancreatic β-cells can be infected by SARS-CoV-2, as T1D is a direct consequence of β-cell depletion. Here, we find that the SARS-CoV-2 receptor, ACE2 and its related entry factors, TMPRSS2, NRP1, and TRFC, are expressed in β-cells, with the latter two selectively present within β-cells. We discover that SARS-CoV-2 has selective cellular tropism for human pancreatic β-cells both ex vivo and in patients with COVID-19. We demonstrate that SARS-CoV-2 infection lowers the abundance of insulin within the pancreas, attenuates glucose-stimulated insulin secretion, and induces β-cell apoptosis. Finally, phosphoproteomic and pathway analysis suggests a SARS-CoV-2 stimulated signature for induction of apoptosis-associated signaling pathways in β-cells, similar to that seen in T1D. Taken together, our study demonstrates that SARS- CoV-2 can directly cause pancreatic islet impairment by killing β-cells, providing a mechanistic explanation for why T1D develops in COVID-19 patients.
2021-07-24 | PXD025629 | Pride
Project description:Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in hepatocyte nuclear factor 1 alpha (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
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Project description:The therapeutic landscape for Type 1 Diabetes (T1D) is rapidly changing as ongoing clinical trials aim to delay beta-cell loss by inhibiting proinflammatory cytokines. However, the precise timing and cellular contexts of cytokine dysregulation remains unknown. We generated the largest existing measurement of gene expression and chromatin accessibility in ~1 million immune cells from the pancreatic lymph nodes and spleens of 34 T1D and non-diabetic organ donors. Our study revealed heightened gene activity of the tumor necrosis factor (TNF) pathway and subsequent chromatin remodeling in central memory CD4+ T cells residing in the pancreatic lymph nodes of T1D and non-diabetic islet-autoantibody positive donors. These findings, validated in mice, offer a mechanism underlying the efficacy of TNF inhibitors, currently undergoing clinical trials to delay T1D onset.
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Project description:Purpose: The goal of this study was the transcriptome high-throughput data analysis of TR3-56 cells isolated from peripheral blood of healthy and T1D subjects Methods: total RNA profile of human TR3-56 cells from healthy and T1D subjects (1. Healthy Subject, 2.Healthy Subject, 3.Healthy Subject; 4. T1D subject, 5. T1D subject, 6. T1D subject; deeep sequencing, using Ovation SoLo RNA-seq Library Preparation KIt (NuGen), Library were prepared for sequencing on NextSeq 500 (llumina technology) Results: Principal component analysis and unsupervised clustering showed that TR3-56 cells from healthy donors are transcriptionally different from TR3-56 cells isolated from T1D subjects. Conclusions: Several genes are differently regulated between TR3-56 cells from T1D and healthy donors.
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Project description:Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cis-splicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-B-restricted vs. HLA-A-restricted CD8+ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and islet-infiltrating CD8+ T-cells from T1D donors were reactive to some HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.
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Project description:We interrogated the transcriptome from bulk-sorted T1D donor β-cells as compared to non-diabetic donors. We found β-cells also expressed mRNA for HLA Class II and Class II antigen presentation pathway components, but not a macrophage marker.
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Project description:Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic b-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-I interferon (IFN) mediated intracellular signalling. To study the role of TYK2 in human pancreatic b-cell development and response to IFNa, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Unexpectedly, loss of TYK2 compromised the emergence of endocrine precursors by regulating KRAS expression, however, mature b-cell function was not affected. In the mature stem cell-derived islets, the loss or inhibition of TYK2 prevented IFNa-induced antigen processing and presentation, including MHC Class I expression, enhancing their survival against T-cell cytotoxicity. These results identify an unsuspected role for TYK2 on b-cell development and support TYK2 inhibition in adult b-cells as a potent therapeutic target to halt T1D progression.
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