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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data comparing adult human islets to human embryonic stem cell-derived insulin-positive and insulin-negative cells

ABSTRACT: The study was completed to compare expression profiles of primary human beta cells (in the form of adult human islets), to the expression profile of hESC-derived beta-like cells. A HES3 line modified by homologous recombination to express GFP under the insulin promoter allowed us to FACS sort the hESC-derived cells into purified insulin-positive (presumably beta-like cells), and insulin-negative populations. Expression profile of adult human islets from cadaveric donors is compared to insulin-positive and insulin-negative populations of hESC-derived beta-like cells

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Wheeler

PROVIDER: E-GEOD-40709 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data comparing adult human islets to human embryonic stem cell-derived insulin-positive and insulin-negative cells

Project description:The study was completed to compare expression profiles of primary human beta cells (in the form of adult human islets), to the expression profile of hESC-derived beta-like cells. A HES3 line modified by homologous recombination to express GFP under the insulin promoter allowed us to FACS sort the hESC-derived cells into purified insulin-positive (presumably beta-like cells), and insulin-negative populations.

2012-09-09 | GSE40709 | GEO

Wnt-modulated hiPSC-derived insulin-producing cells, adult human islet proteome

Project description:We aimed to assess whether Wnt-modulation could contribute to mature hiPSC-derived insulin-producing cells in vitro. Building our hypothesis on our previous findings of Wnt activation in immature hiPSC-derived insulin-producing cells compared to adult human islets and with recent data reporting a link between Wnt/PCP and in vitro beta-cell maturation. In this study we stimulated hiPSC-derived insulin-producing cells with syntetic proteins including WNT3A, WNT4, WNT5A and WNT5B as well as inhibiting endogeneous Wnt signaling with Tankyrase inhibitor G007-LK.

2019-11-13 | PXD012081 | Pride

Transcriptional profiling by array of INSULIN-expressing cells derived from INS-GFP human embryonic stem cells under different differentiation and culture conditions

Project description:Differentiation of INSGFP/w hESCs using published protocols demonstrated that all GFP+ cells co-expressed insulin, confirming the fidelity of the reporter gene. INS-GFP+ cells also co-expressed glucagon and somatostatin, confirming prior studies regarding the polyhormonal nature of early hESC derived insulin-expressing cells. INSGFP/w hESCs were employed to develop a 96 well format spin Embryoid Body (EB) differentiation protocol that utilized the recombinant protein based fully defined medium, APEL. Like INS-GFP+ cells generated with other methods, those derived using the spin EB protocol expressed a collection of pancreatic related transcription factors including ISL1, PAX6 and NKX2.2. However, in contrast to previous methods, the spin EB protocol yielded INS-GFP+ cells that also co-expressed the beta-cell transcription factor, NKX6.1 and comprised a substantial proportion of monohormonal insulin+ cells.

2012-02-02 | E-MEXP-3378 | biostudies-arrayexpress

Insulin deficiency distorts human pancreatic endocrine cell composition during development

Project description:Objective: The developmental effects of mutations in genes associated with monogenic diabetes on human pancreas development is not well understood. More specifically, if insulin gene recessive mutations influence the human endocrine lineage segregation still needs to be investigated. Methods: We generated a novel knock-in H2B-Cherry reporter human induced pluripotent stem cell (iPSCs) line expressing no insulin upon differentiation to stem cell-derived (SC-) β cells in vitro. This cell line enabled us to have a model mimicking the extremely reduced insulin levels in patients with recessive insulin mutations. We combined immunostaining, Western blotting and proteomics analysis to characterize the SC-islets from this iPSC line. Furthermore, we leveraged FACS analysis and imaging to explore the impact of insulin shortage on human endocrine cell induction, composition and proliferation. Results: We found that lack of insulin hampers insulin receptor (IR) signaling in SC-islets but increases the IR sensitivity. Furthermore, insulin deficiency showed no effects on human endocrine lineage induction. However, lack of insulin skewed the SC-islet cell composition. We found an increased in SC-β cell number at the expense of SC-α cell differentiation in the absence of insulin. Finally, insulin shortage reduced the rate of SC-β cell proliferation but had no impact of the expansion of SC-α cells. Conclusions: We provided evidence of the developmental impacts of reduced insulin levels on human β cell characteristics and endocrine lineage formation. These findings help to better understand the pathomechanisms of recessive insulin mutations during embryonic development and also shed some lights on the possible physiological function of this hormone coordinating human islet cell composition and architecture during endocrinogenesis.

2024-01-17 | PXD045366 | Pride

Gene expression data from Min6 cells grown in serum containing and serum free condtions following Hes3 knock down

Project description:The basic helix-loop-helix (bHLH) transcription factor hairy and enhancer of split (Hes3) is a member of the Hes/Hey gene family that regulates developmental processes in progenitor cells from various tissues. We demonstrated the Hes3 expression in mouse pancreatic tissue, suggesting it may have a role in modulating beta-cell function. We employed a transfection approach to address specific functions of Hes3. Hes3 RNA interference opposed the growth of the mouse insulinoma cell line Min6. Western blotting and PCR approaches specifically showed that Hes3 RNA interference opposes the expression of Pdx1 and insulin. Likewise, Hes3 knock down reduced evoked insulin release from Min6 cells.

2014-12-23 | GSE64449 | GEO

A circular RNA generated from an intron of the insulin gene controls insulin secretion

Project description:Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder.

2020-09-21 | GSE134699 | GEO

Checkpoint Kinase 2 Controls Insulin Secretion and Glucose Homeostasis

Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.

2023-10-25 | GSE239335 | GEO

Gene expression data from Min6 cells grown in serum containing and serum free condtions following Hes3 knock down

2014-12-23 | E-GEOD-64449 | biostudies-arrayexpress

Insulin secretory granules release exosomal miR-503 to promote insulin resistance and β-cell senescence.

Project description:Since β cell specific miR-503 transgenic (βTG) mice showed metabolic stress induced insulin resistance and β cell dysfunction, we applied single cell sequencing (scSeq) technology to distinguish different cell type in β TG islets and define different phases of β cell subtypes through pseudotime analysis. Islets were isolated and digested at 37℃for 5 min by 0.08 % trypsin containing 0.006 % EDTA to generate islet single cell, cell suspension was centrifuged and resuspended in cold PBS buffer with 0.4% of BSA at the concentration of ~1000/μl, which then was loaded onto the 10X Chromium Controller using Chromium Single Cell 3’ v2 reagents. Sequencing library was prepared following the manufacturer’s instructions (10X Genomics), and sequenced via a Illumina HiSeq PE150 instrument. 8698 cells were detected from 10-week old wild type (WT, n = 4540 cells) and βTG (n = 4158 cells) mice islets, cells were split to 12 subtypes by using cell ranger software and k-means algorithm. According to specific gene profile we found that βTG islets was infiltrated with Ccr6/Ccr7 positive immune cells, and most β cells in βTG mice islets were defined senescent cells by using GO enrichment and pseudotime analysis. Our study represents the analysis of islet single cell transcriptomes, the results showed that miR-503 highly expression in β cells promotes β cell senescence and diabetes onset.

2022-07-08 | GSE155798 | GEO

Reduced basal insulin secretion from islets isolated from tafazzin deficient mice is associated with reduced mitochondrial function

Project description:Tafazzin is a transacylase which causes the content and molecular structure of cardiolipin (CL) to be altered in the inner mitochondrial membrane. The enzymatic machinery responsible for oxidative respiration are localized to the inner mitochondrial membrane and require CL for activity. As a result, tafazzin is critical for maintaining mitochondrial function. In beta-cells, which are the insulin secreting cells in pancreatic islets, mitochondrial function is linked to insulin secretion. We previously established that tafazzin knock-down mice were lean and maintained insulin sensitivity compared to the obese insulin resistant control litter mates. However, it was unknown whether tafazzin deficiency also influenced insulin secretion in the establishment of the lean phenotype. Using X week-old mice, we ascertained that the number of beta-cells was similar between genotypes. Ex vivo insulin secretion under low glucose conditions was reduced (52%) from islets isolated from tafazzin knock-down mice. Consistent with this tafazzin knock-down mice exhibited reduced fasting insulin plasma insulin levels. Measurement of mitochondrial oxygen consumption revealed that basal oxygen consumption was reduced (58%) in islets from tafazzin-deficient animals. The addition of etomoxir, an inhibitor of mitochondrial fatty acid translocation, significantly elevated basal mitochondrial respiration (5-fold) in islets from tafazzin knockdown mice, indicating a significant fatty acid-mediated inhibitory effect. In contrast, etomoxir lacked any measurable effect on control wild-type islets. The altered mitochondrial function identified in taffazin knock-down islets was not associated with reduced CL content or elevated oxyCL species. Our experiments indicate that tafazzin plays a key role in regulating normal islet beta-cell function.

2021-07-31 | GSE136242 | GEO

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