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Transcriptomics and single-cell RNA sequencing analysis of long-term cultured human islets in vitro [RNA-Seq]

ABSTRACT: β-cell dysfunction in pancreatic islets is the leading cause of progression to type I diabetes (T1D), but the reason for the loss of β-cell mass in T1D is still not fully understood. Using in vitro long-term cultured (LTC) human islets, we have investigated gene profiling and subtype cells changes in the leftover cells and compared them with residual cells in samples of T1D or T2D. While most of the dysregulated genes were downregulated during LTC, we found there are specific groups of mRNA or miRNA that were upregulated, and they are involved in specific pathways. In general, α-cells and β-cells of LTC-islets have elevated expressions of MAFB and MAFA, respectively. We also found exocrine cells were eliminated faster than endocrine cells, and β-cells were lost at a higher rate than α-cells. Interestingly, a specific group of cells that were classified as α-cells but have immature β-cells-like characteristics, were enriched in LTC, revealed the possibility of transdifferentiating of α-cells to β-cells under in vitro culture. Our results suggested that there are intrinsic cellular and molecular mechanisms in pancreatic cells that are associated with their maturity and correlated with their survival ability under unfavorable living conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280983 | GEO | 2025/01/15

REPOSITORIES: GEO

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Transcriptomics and single-cell RNA sequencing analysis of long-term cultured human islets in vitro [scRNA-Seq]

Project description:β-cell dysfunction in pancreatic islets is the leading cause of progression to type I diabetes (T1D), but the reason for the loss of β-cell mass in T1D is still not fully understood. Using in vitro long-term cultured (LTC) human islets, we have investigated gene profiling and subtype cells changes in the leftover cells and compared them with residual cells in samples of T1D or T2D. While most of the dysregulated genes were downregulated during LTC, we found there are specific groups of mRNA or miRNA that were upregulated, and they are involved in specific pathways. In general, α-cells and β-cells of LTC-islets have elevated expressions of MAFB and MAFA, respectively. We also found exocrine cells were eliminated faster than endocrine cells, and β-cells were lost at a higher rate than α-cells. Interestingly, a specific group of cells that were classified as α-cells but have immature β-cells-like characteristics, were enriched in LTC, revealed the possibility of transdifferentiating of α-cells to β-cells under in vitro culture. Our results suggested that there are intrinsic cellular and molecular mechanisms in pancreatic cells that are associated with their maturity and correlated with their survival ability under unfavorable living conditions.

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Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

Project description:Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled >40,000 cells from normal human islets by scRNA-seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells co-expressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-seq, MAFA/MAFB co-expressing β cells showed enhanced electrophysiological activity. Thus, these results indicate combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.

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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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