Stage-specific transcriptomic changes in α-cells after massive β-cell loss
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PROVIDER: PRJNA649978 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description:We aimed to fill the gap in understanding functional roles of the islet cellular oscillators under diabetic conditions following massive β-cell ablation, and during β-cell regeneration. We assessed diurnal regulation of β-cell proliferation and transcriptional landscape in separated α- and residual β-cells -utilizing rtTA/TET-DTA mouse model that bears α- and β-cell specific labeling. 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 knockout mice, massive β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia and a fatal non-compensated diabetes. No activation of β-cell regeneration via entry into cell-cycle was observed in arrhythmic mice, suggesting essential role of functional circadian clocks in this process.
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Project description:After their destruction in adult mice, insulin-producing pancreatic beta-cells slowly regenerate from other islet cells, like glucagon-producing alpha-cells. However the molecular basis of this conversion is unknown. Moreover it remains unclear if this intra-islet cell conversion is relevant to human diseases with extensive beta-cell loss, like in type 1 diabetes (T1D). Here, we show that subsets of glucagon-expressing cells in subjects with T1D produce Insulin and other molecular features of beta-cells, accompanied by loss of the alpha-cell regulators DNA methyltransferase 1 (Dnmt1) and Aristaless-related homeobox (Arx). We generated mice permitting lineage tracing and inactivation of Dnmt1 and Arx in adult alpha-cells. Within 3 months of Dnmt1 and Arx loss, 50% of alpha-cells converted into cells producing insulin protein but not glucagon, changes not observed in alpha-cells after only Arx or Dnmt1 loss. Single cell isolation and high-throughput RNA sequencing revealed efficient and extensive alpha-cell conversion into progeny indistinguishable by global gene expression from native beta-cells. Our work reveals pathways regulated by Arx and Dnmt1 sufficient for achieving targeted generation of beta-cells from adult pancreatic alpha-cells.
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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.
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Project description:Rodent models are widely used to study diabetes. Yet, significant gaps remain in our understanding of mouse islet physiology that reduce their accuracy as a model for human islet disease. We generated comprehensive transcriptomes of mouse beta and alpha cells using a novel bitransgenic mouse model generated for this purpose. This enables systematic comparison across thousands of genes between the two major endocrine cell types of the islets of Langerhans whose principal hormones are of cardinal importance for glucose homeostasis. Our data leveraged against similar data for human beta cells reveal a core common beta cell transcriptome of 9900+ genes and marked differences in the repertoire of receptors and long non-coding RNAs between mouse and human beta cells. The comprehensive comparison of the (dis)similarities between mouse and human beta cells represents an invaluable resource to boost the effectiveness by which rodent models offer guidance in finding cures for human diabetes. FACS purified alpha and beta cells from the same islets. Islets were isolated from bitransgenic offspring of a cross between mIns1-H2b-mCherry and S100b-eGFP transgenic reporter mice that mark beta and alpha cells, respectively. Islets from two replicate groups of 10 or 11 animals were pooled by sex to obtain sufficient material. Pooled islets were dissociated, sorted and collect in Trizol for RNA isolation and library construction.
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Project description:MicroRNAs (miRNAs) are non-coding RNAs that play a fundamental role in regulation of gene expression affecting differentiation and development. In particular, miRNAs have been described to regulate genes important for pancreatic development and islet function. The aim of this work was to determine the miRNA expression signature in human pancreatic alpha and beta cells. miRNA stability to fixation allowed the study of microRNA in pure populations of human alpha and beta cells sorted by FACS after intracellular staining with glucagon and insulin, respectively. The determination of the specific group of miRNAs expressed in the human pancreatic alpha and beta cells may further the understanding of gene expression regulation of the islet differentiation process. The alpha and beta cells come from 6 different preparations of human pancreatic islets from donors. In this study we define expression profiles of a total of 665 miRNAs for pancreatic alpha and beta cells. For this purpose, cells were fixed with paraformaldehyde, 7AAD was applied to exclude dead cells. Then, cells were sorted after intracellular staining with C peptide to detect beta cells and glucagon to detect alpha cells. After sorting, we confirmed enriched beta cells have a purity of on average over 98%. Enriched alpha cells have a purity of on average over 98%. To determine the miRNA expression profiles, we used human miRNA TLDAs version 2. For each sample card A and card B were run after cDNA synthesis and 12 cycles of preamplification according to the manufacturer protocol. Each TLDA card A contains 1 probe for the endogenous control RNU48 while each TLDA card B contains 4 replicates of the RNU48 probe. Analysis of these controls allows calculating the intra- and inter-assay variation. Quantitative values (RQ) were calculated measuring the ddCt between the Ct values of each miRNA and the Ct value of the small nucleolar RNU48 RNA comparing the target sample and the control sample.
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