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Stage-specific transcriptomic changes in α-cells after massive β-cell loss

ABSTRACT: Conversion of α-cells into insulin-producers upon β-cell loss is modulated by constitutive signals ensuring α-cell identity maintenance. Here, we characterized the plasticity of mouse α-cells by profiling their transcriptome at different time-points after massive β-cell ablation. Our results show that α-cells undergo stage-specific transcriptional changes 5- and 15-days post-diphtheria toxin (DT)-mediated β-cell ablation. At 5 days, α-cells transiently upregulate various genes associated with interferon signaling and proliferation, including Interferon Induced Protein with Tetratricopeptide Repeats 3 (Ifit3). Subsequently, at 15 days post β-cell ablation, α-cells undergo a transient downregulation of genes from several pathways including Insulin receptor, mTOR and MET signaling. These results pinpoint novel markers discriminating α-cells at different stages after acute β-cell loss, and highlight additional signaling pathways that could be involved in reprogramming the functional identity of α-cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE155519 | GEO | 2021/04/27

REPOSITORIES: GEO

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Pancreatic Ppy-expressing gamma-cells display mixed phenotypic traits and adaptive plasticity to engage insulin production

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.

2021-06-04 | GSE156665 | GEO

Pancreatic Islet-Autonomous Signals Modulate Identity Changes of Glucagon+ α-Cells

Project description:The mechanisms restricting regeneration and maintaining cell identity upon injury are poorly characterized in higher vertebrates. Upon β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage insulin production in mice. Here we explore the mechanisms of this plasticity. We show that the adaptive α-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. Combining β-cell loss, or insulin signaling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that removing constitutive “brake signals” is crucial for neutralizing the refractoriness to adaptive cell-fate changes. It appears that cell identity maintenance is an active process mediated by repressive signals curbing an intrinsic trend of differentiated cells to change.

2018-06-18 | GSE109285 | GEO

Diabetes Remission Using Glucose-Responsive Insulin-Producing Human α-Cells

Project description:Natural and stable cell identity switches, where terminally-differentiated cells convert into different cell-types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells become insulin expressers upon ablation of insulin-secreting β-cells, promoting diabetes recovery. Whether human islets also display this plasticity for reconstituting β-like cells, especially in diabetic conditions, remains unknown. Here we show that two different islet non-β-cell types, α- and γ–cells, obtained from deceased non-diabetic or diabetic human donors can be lineage-traced and induced to produce insulin and secrete it in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and remain producing insulin even after 6 months. Insulin-producing α-cells maintain α-cell markers, as seen by deep transcriptomic and proteomic characterization, and display hypo-immunogenic features when exposed to T-cells derived from diabetic patients. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity in islet cells, as well as in other organs, as a therapy for degenerative diseases by fostering the highly-regulated intrinsic cell regeneration.

2018-12-13 | GSE117454 | GEO

Diabetes Remission Using Glucose-Responsive Insulin-Producing Human alpha-Cells

2018-12-15 | GSE123844 | GEO

Circadian clocks drive regeneration of pancreatic β-cells in mice

Project description:We aimed to understand the functional roles of islet cellular oscillators under diabetic conditions and during β-cell regeneration. We assessed diurnal regulation of β-cell proliferation and the transcriptional landscape in α- and residual β-cells following β-cell ablation in Insulin-rtTA/TET-DTA mice that simultaneously expressed α- and β-cell specific fluorescent reports. The mouse pancreatic islets were isolated over 24-h with 4-h interval, followed by separation of α- and β- cells using FACS sorting, RNA extraction and RNA sequencing. Acute hyperglycemia and loss of β-cell mass perturbed absolute expression levels and temporal transcriptome profiles in residual β-cells, whereas in neighboring α-cells only changes in temporal profiles were observed. Strikingly, compensatory regeneration of β-cells exhibited circadian rhythmicity. In arrhythmic Bmal1 deficient mice, massive β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia and a fatal diabetes. No compensatory proliferation of β-cells was observed in arrhythmic mice, suggesting an essential role of circadian clocks in β-cell regeneration.

2020-10-16 | GSE152751 | GEO

Generation of Human Islet Cell-Type-Specific Identity Genesets

Project description:Generation of mature cells with stable functional identities is crucial for developing cell-based replacement therapies. Current global efforts to produce insulin-secreting beta-like cells to treat diabetes are hampered by the lack of tools to reliably assess cellular identity. We conducted a thorough single-cell transcriptomics meta-analysis to generate robust genesets defining the identity of human adult alpha-, beta-, gamma- and delta-cells. After extensive validation, we showed the efficacy of the novel genesets to define changes in islet cell identity, whether during embryonic development or in different experimental setups aimed at developing new functional glucose-responsive insulin-secreting cells, such as through pluripotent stem-cell differentiation or islet cell reprogramming protocols. Finally, we evaluated whether the perturbed metabolic conditions typical of diabetes influence islet cell identity. We observed that alpha-cells from diabetic donors exhibit an altered phenotype. In conclusion, these novel genesets represent valuable tools that robustly benchmark gain and loss in islet cell identity traits.

2021-06-26 | GSE150724 | GEO

Expression data from GW8510 treatment of pancreatic cells

Project description:Expression of insulin in terminally differentiated non-beta pancreatic cell types could be important for treating type-1 diabetes. We observed that the kinase inhibitor GW8510 up-regulated insulin expression in mouse pancreatic alpha cells. Gene-expression profiling and gene-set enrichment analysis of GW8510-treated alpha cells suggested coordinate up-regulation of the p53 pathway, which was further implicated in induction of insulin transcript. In order to determine a potential mechanism of insulin induction by GW8510, we treated mouse alpha cells (aTC1) and beta cells (bTC3) with 3.3 µM GW8510 or 0.1% DMSO for five days, and performed gene-expression profiling followed by gene-set enrichment analysis (GSEA). Three biological replicates were included per condition. GW8510 treatment in each cell line was compared to DMSO-treated control.

2011-08-01 | E-GEOD-31102 | biostudies-arrayexpress

Gene expression profiling of MafA, MafB, and MafA/MafB Mutants in E18.5 pancreas

Project description:MafA and MafB transcription factors have been shown to be key regulators of insulin and glucagon transcription. MafB is essential for alpha and beta cell differentiation, as MafB deficient mice produced fewer insulin+ and glucagon+ cells during development, with MafA expressed in remaining insulin+ cells. In contrast, beta cell development was reported to be normal in a total MafA knock out, although the animals developed beta cell dysfunction and diabetes as adults. However, we have found that MafB expression is elevated during development and retained in adult insulin+ cells after conditional removal of MafA in the pancreas. These studies will evaluate the broader significance of these insulin and glucagon regulators in alpha and beta cell development and function. Our efforts will focus on determining if the concerted actions of MafA and MafB factors are significant to beta cell formation, and we specifically plan to: Determine how alpha and beta cell differentiation is affected in MafA/MafB compound mutant mice during pancreas development. cDNA microarray studies (pancchip 6.0) with wild type, MafAKO, MafB-/-, and MafAKOMafB-/- mutant E18.5 pancreata will be performed to comprehensively identify genes controlled by MafA and MafB in developing alpha and beta cells.

2014-11-04 | E-MTAB-3070 | biostudies-arrayexpress

Transcriptome comparison of PAX6 ablated mouse beta cells to WT beta cells, ChIP-seq analysis of PAX6 bound sites both in mouse and human beta cell lines (Min6 and EndoC), and ChIP-seq analysis fo histone mark H3K9ac on mouse pancreatic beta cells.

Project description:Here, we report a key role for the transcription factor Pax6 in the maintenance of adult beta-cell identity and function. Pax6 is down regulated in beta-cells of diabetic db/db mice and in wild type mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in beta-cells of adult mice leads to lethal hyperglycemia and ketosis, due to loss of beta-cell function and expansion of alpha-cells. Lineage tracing, transcriptome, and chromatin analyses show that Pax6 is a direct activator of beta-cell genes, maintaining mature beta-cell function and identity. In parallel, Pax6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicate a similar function of PAX6 in human beta-cells. Reduced expression of Pax6 in metabolically stressed beta-cells may contribute to beta-cell failure and alpha-cell dysfunction in diabetes.

2016-11-01 | GSE87530 | GEO

The leptin receptor has no role in delta-cell control of beta-cell function in the mouse

Project description:Introduction: Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Several mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) throughout the pancreatic epithelium results in altered glucose homeostasis and ex vivo insulin secretion and Ca2+ dynamics. However, Lepr removal from neither alpha nor beta cells mimics this result. Moreover, scRNAseq data has revealed an enrichment of LEPR in human islet delta cells. Methods: We confirmed LEPR upregulation in human delta cells by performing RNAseq on fixed, sorted beta and delta cells. We then used a mouse model to test whether delta cells mediate the diminished glucose-stimulated insulin secretion in response to leptin. Results: Ablation of Lepr within mouse delta cells did not change glucose homeostasis or insulin secretion, whether mice were fed a chow or high-fat diet. We further show, using a publicly available scRNAseq dataset, that islet cells expressing Lepr lie within endothelial cell clusters. Conclusions: In mice, leptin does not influence beta-cell function through delta cells.

2023-10-02 | GSE243984 | GEO

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