E-MTAB-7234
Ontology highlight
ABSTRACT:
PROVIDER: E-MTAB-7234 | ExpressionAtlas | 2018-11-12
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-MTAB-7234-analysis-methods.tsv | Tabular | |||
| E-MTAB-7234-analytics.tsv | Tabular | |||
| E-MTAB-7234-atlasExperimentSummary.Rdata | Rdata | |||
| E-MTAB-7234-configuration.xml | Xml | |||
| E-MTAB-7234-g2_g1-mvaPlot.png | Other |
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Project description:RNA-seq of islet, FACS- sorted CD45+Ly6C-CD11B+CD11C+F4/80+ cells from C57bl6/J male mice that were treated with low dose streptozotocin (STZ) or acetate buffer
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Project description:The experiment was designed to obtain a broader unbiased view of the changes in islet macrophages following low dose STZ challenge. Mice were purchased from Jackson Laboratory (Bar Harbor, ME). 16-20-week-old C57BL/6J males were given 30 mg/kg STZ or acetate buffer (control) i.p. (intraperitoneal injection) for 5 consecutive days. Following the first STZ or buffer injection mice were sacrificed on day 14 and islets were isolated by collagenase digestion. Freshly isolated islets were dispersed in 0.02% Trypsin-EDTA for 3 minutes followed by up to 1 minute of pipetting under a stereomicroscope to obtain a single cell solution. Islet media was added to stop the reaction. Islets from 10 mice were pooled per sample (N). Dispersed islets were washed with FACS buffer (1% heat inactivated FBS, 1 mM EDTA, 11 mM glucose in PBS). Cells were kept on ice and pre-incubated with Fc Block (1:100) for 5 minutes, followed by 30 min incubation with CD45-eFluor 450 (1:250; clone 30-F11), Ly-6C-APC (1:1,200; clone HK1.4), CD11b-PE (1:1,200; clone M1/700, F4/80-FITC (1:150; clone BM8), CD11c-PECy7 (1:150; clone N418), and the viability dye 7AAD (1:2,000). Unstained, single stains, and fluorescence minus one controls were used for setting gates and compensation. Viable, single CD45+Ly6c-Cd11b+Cd11c+F4/80+ cells were sorted using a BD FACS Aria IIu directly into lysis buffer, and the RNeasy Plus Micro Kit from Qiagen was used to isolate total RNA. Total RNA quality control quantification was performed using an Agilent 2100 Bioanalyzer. All RNA samples had an RNA integrity number (RIN) ≥9.1. The NeoPrep Library Prep System from Ilumina was used for library preparation followed by sequencing using standard Illumina methods and Ilumina NextSeq500.
2019-11-01 | E-MTAB-7234 | biostudies-arrayexpress
Project description:To further examine the mechanisms of urate in islet β-cell death, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish primacy of streptozotocin (STZ) vs. urate. Islets were isolated from Uox-KO and WT mice with and without multiple low-dose STZ. Differentially expressed genes (DEGs) in islets of the hyperuricemic and/or diabetic mice in comparison to their respective controls represented specific Gene Ontology (GO) pathways and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional meanings.
2020-05-04 | GSE142421 | GEO
Project description:Objectives The streptozotocin (STZ) model is widely used in diabetes research. However, the cellular and molecular states of pancreatic endocrine cells in this model remain unclear. This study explored the molecular characteristics of islet cells treated with STZ and re-evaluated β-cell dysfunction and regeneration in the STZ model. Methods We performed single-cell RNA sequencing of pancreatic endocrine cells from STZ-treated mice. High-quality sequencing data from 2,999 cells were used to identify clusters via Louvain clustering analysis. Principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), uniform manifold approximation and projection (UMAP), force-directed layout (FDL), and differential expression analysis were used to define the heterogeneity and transcriptomic changes in islet cells. In addition, qPCR and immunofluorescence staining were used to confirm findings from the sequencing data. Results Untreated β-cells were divided into two populations at the transcriptomic level, a large high-Glut2 expression (Glut2high) population and a small low-Glut2 expression (Glut2low) population. At the transcriptomic level, Glut2low β-cells in adult mice did not represent a developmentally immature state, although a fraction of genes associated with β-cell maturation and function were downregulated in Glut2low cells. After a single high-dose STZ treatment, most Glut2high cells were killed, but Glut2low cells survived and over time changed to a distinct cell state. We did not observe conversion of Glut2low to Glut2high β-cells up to 9 months after STZ treatment. In addition, we did not detect transcriptomic changes in the non-β endocrine cells or a direct trans-differentiation pathway from the α-cell lineage to the β-cell lineage in the STZ model. Conclusions We identified the heterogeneity of β-cells in both physiological and pathological conditions. However, we did not observe conversion of Glut2low to Glut2high β-cells, transcriptomic changes in the non-β endocrine cells, or direct trans-differentiation from the α-cell lineage to the β-cell lineage in the STZ model. Our results clearly define the states of islet cells treated with STZ and allow us to re-evaluate the STZ model widely used in diabetes studies.
2020-04-23 | GSE137909 | GEO
Project description:We aim to investigate the role of renal Sirt1 on albuminuria. To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between wild type(C57BL/6J) mice treated with streptozotocin (WT+STZ) and Sirt1-overexpressing transgenic mice treated with streptozotocin (TG+STZ) mice. To elucidate the molecular mechanisms underlying the amelioration of albuminuria by our TG (Sirt1-overexpressing transgenic) mice, we performed DNA microarray analysis using micro-dissected glomerular regions to examine the differences in gene expression between WT+STZ and TG+STZ mice.
2018-03-08 | GSE50140 | GEO
Project description:The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Considering the fact that MASLD patients accompanying type 2 diabetes mellitus (T2DM) have high risk of developing metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, and HCC, we treated low-dose streptozotocin (STZ; 40 mg/kg) for 5 consecutive days and subsequently fed a high-fat diet (HFD) to male C57BL/6J mice at 7 weeks of age (STZ+HFD). STZ+HFD mice gradually developed fatty liver, MASH, hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. In particular, from 20 weeks of age, MASH was evident, and from 32 weeks of age, advanced fibrosis was developed. At 38 weeks, a proportion of STZ+HFD mice developed HCC, which was subsequently observed in all mice up to 68 weeks of age. Furthermore, the hepatic transcriptomic features of STZ+HFD mice closely reflected those of obese patients with T2DM, MASH and MASLD-related HCC. Notably, dietary changes and tirzepatide administration alleviated MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ+HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients with metabolic dysfunction was successfully established.
2024-06-17 | GSE246221 | GEO
Project description:The lack of an appropriate preclinical model of non-alcoholic fatty liver disease (NAFLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Therefore, we developed new mose model with Streptozotocin (STZ)and high-fat diet (HFD). In breif, male C57BL/6J mice were injected with low-dose streptozotocin (40 mg/kg) for 5 consecutive days beginning at 7 weeks of age and subsequently fed a high-fat diet from week 8 (STZ+HFD) onwards. Hepatic histopathology, transcriptomics, epigenetics, and metabolic phenotypes were evaluated at various time-points. The hepatic transcriptomes of STZ+HFD mice and NAFLD patients with similar liver histopathology were compared. In STZ+HFD mice, dietary changes from HFD to standard chow and administration of tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, were introduced to assess the therapeutic efficacy of these interventions. STZ+HFD mice gradually developed fatty liver, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. In particular, from 32 weeks of age, NASH and advanced fibrosis were evident. At 38 weeks, a proportion of STZ+HFD mice developed HCC, which was subsequently observed in all mice up to 68 weeks of age. Furthermore, the hepatic transcriptomic features of STZ+HFD mice closely reflected those of patients with NASH and NAFLD-related HCC. Notably, dietary changes and tirzepatide administration alleviated NASH, hepatic fibrosis, and hepatic tumorigenesis in STZ+HFD mice. Put together, we established a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in NAFLD patients with metabolic dysfunction was successfully established.
2024-06-17 | GSE246213 | GEO
Project description:Leptin monotherapy (i.e. without the use of administered insulin and/or any other molecule) corrects ID-induced metabolic aberrancies and promotes survival of insulin deficient rodents. These results generated great interest in the possibility of treating insulin deficient patients with leptin and/or molecule(s) underlying its beneficial effects. Hence, with the goal of identifying circulating molecule(s) underlying the advantageous effect of leptin we performed quantitative proteomic analysis of plasma and identified S100A9 as a putative peripheral mediator of leptin action. Here, to identify circulating molecule(s) underlying the advantageous effect of leptin we compared the results obtained by quantitative proteomic analysis of plasma between 2 groups of mice: streptozotocin (STZ)-treated mice that underwent intracerebroventricular (icv) leptin treatment for 12 days (STZ-Leptin) and ii) STZ-treated mice that underwent icv leptin treatment for 10 days and were withdrawn from leptin treatment for the following two days (STZ-Leptin-STOP). STZ treatment led to a massive loss of pancreatic insulin-producing β-cells, diminished pancreatic Proinsulin mRNA level, and caused severe insulinopenia, and hyperglycemia. icv leptin administration normalized hyperglycemia. However, two days after leptin delivery was halted hyperglycemia reappeared. We hypothesized that change in plasmatic protein(s) content could underlie re-emergence of hyperglycemia following decrease of leptin action.
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Project description:Streptozotocin (STZ) is an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings and develop type 1 diabetes rodent models in experimental fields. STZ is incorporated into cells through the glucose transporter, GLUT2, which is primarily expressed in pancreatic β-cells or proximal tubular epithelial cells in the kidney. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of tubular epithelial cells in vitro showed the activation of the p53 signaling pathway by STZ. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transport. The localization of STZ-induced kidney injury was limited to within the kidney cortex, which was independent of blood glucose. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the strong proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo, which may be ameliorated by a SGLT2 inhibitor pretreatment. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, a pretreatment with a SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.
2023-06-07 | GSE215337 | GEO
Project description:Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes. Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes. Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes.
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