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Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages

ABSTRACT: Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages

PROVIDER: PRJNA951441 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24044045_1.fastq.gz	Fastqsanger.gz
	SRR24044045_2.fastq.gz	Fastqsanger.gz
	SRR24044046_1.fastq.gz	Fastqsanger.gz
	SRR24044046_2.fastq.gz	Fastqsanger.gz
	SRR24044047_1.fastq.gz	Fastqsanger.gz

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Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages

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Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.

Project description: Not available

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Human iPSC-based Modeling of Late-Onset Disease using Progerin-induced Aging

Project description:Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features. Induced pluripotent stem cell-derived midbrain dopamine neurons from a young and old donor overexpressing either GFP or Progerin.

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Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells

Project description:Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells

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Treatment with ginseng flower buds extract prevents hepatic steatosis by ameliorating hepatic inflammation and insulin resistance

Project description:Background: Ginseng flower bud (GFB) is a part of ginseng with high content of ginsenosides, the known active components of ginseng. While the scientific data for the pharmacological activity of ginseng roots are accumulating, the therapeutic potential of GFB have been neglected. The current study aimed to examine the therapeutic effect of GFB on hepatic steatosis and to elucidate the underlying mechanisms. Methods: HepG2 cells treated with free fatty acids mixture and hepatocytes isolated from rats after 3 weeks of HFD feeding were used as in vitro models of hepatic steatosis for evaluation of anti-steatotic effect of GFB. The effect of GFB was further investigated in pathological conditions of hepatic steatosis induced by 12 weeks of HFD feeding in C57BL/6J mice. We performed systematical analyses on hepatic gene expression profiles in GFB treated mice. The effect of GFB on the expression profile of selected genes was validated by quantitative PCR. Results: GFB treatment markedly reduced oil red O stained lipid droplets and intracellular triglyceride levels in HepG2 cells and rat hepatocytes. In HFD-fed mice, GFB (500 mg/kg) treatment markedly reduced histological signs of hepatic steatosis and decreased hepatic triglyceride content by 34.1% compared to those of HFD. These changes by GFB treatment were accompanied by improved insulin signaling. Global gene expression analysis revealed that hepatic gene expression in the steatotic liver was reversed by GFB treatment, and the GFB-regulated genes are involved in immune process, insulin response and lipid storage. Conclusion: These findings provide a substantial evidence for the medicinal use of GFB in prevention or treatment of NAFLD through suppression of hepatic inflammation and fatty acid uptake while sensitizing hepatic insulin signaling

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Project description:Many liver pathologies ranging from cancer to genetic metabolic diseases are amenable to cellular replacement therapies. One of the main difficulties associated with cellular therapy approaches is the generation and expansion of mature autologous hepatocytes. The ability to derive patient-specific induced pluripotent stem cells (iPSCs) have solved the problem of generating autologous cells but differentiation and expansion of mature hepatocytes remain a challenge. Here, we report the generation of human iPSC-derived hepatic organoid (eHEPO) culture system for producing functional hepatocytes using EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within two weeks and expanded long-term without any lose of differentiation capacity to mature hepatocyte (>12 months with passage number 25) and are resilient to freeze-thaw cycles. The hepatic identity of eHEPOs was confirmed by morphological analyses, expression of mature hepatocyte markers and in vitro functional assays. Extensive global transcriptome analyses of all intermediate stages demonstrated the stepwise differentiation iPSCs to mature hepatocytes in endoderm-derived organoids. Finally, starting form patient-specific iPSCs, we created an organoid-based model of Citrullinemia type 1, an inherited urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASS1) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild type ASS1 gene which also indicated that this model is amenable to genetic manipulation. Our results demonstrate that iPSC-derived EpCAM-positive endodermal cells are excellent cell sources to generate patient-specific hepatic organoids in a fast and efficient manner.

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Disruption of the phosphate transporter Pit1 in hepatocytes improves glucose metabolism and insulin signalling by modulating the USP7/IRS1 interaction.

Project description:The liver plays a central role in whole-body lipid and glucose homeostasis. Increasing dietary fat intake results in increased hepatic fat deposition, which is associated with a risk for development of insulin resistance and type 2 diabetes. In this study, we demonstrate a role for the phosphate inorganic transporter 1 (PiT1/SLC20A1) in regulating metabolism. Specific knockout of Pit1 in hepatocytes significantly improved glucose tolerance and insulin sensitivity, enhanced insulin signalling, and decreased hepatic lipogenesis. We identified USP7 as a PiT1 binding partner and demonstrated that Pit1 deletion inhibited USP7/IRS1 dissociation upon insulin stimulation. This prevented IRS1 ubiquitination and its subsequent proteasomal degradation. As a consequence delayed insulin negative feedback loop and sustained insulin signalling were observed. Moreover, PiT1-deficient mice were protected against high fat diet-induced obesity and diabetes. Our findings indicate that PiT1 has potential as a therapeutic target in the context of metabolic syndrome, obesity, and diabetes.

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Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells (scRNA-Seq)

Project description:Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysfunction and Cellular Heterogeneity in PiMZ and PiZZ Hepatic Cells (scRNA-Seq)

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Identification of a novel subset of hepatocytes that are simultaneously gluconeogenic and de novo lipogenic in the fed state and are naturally insulin resistant

Project description:It is generally accepted that hepatic gluconeogenesis, the synthesis of glucose from other carbon substrates (i.e.: glycerol, pyruvate, amino acids), is active in the fasted state and inactive in the fed state. In contrast, de novo lipogenesis (synthesis of fatty acids) is active in the fed state and is inactive in the fasted state. However, RNAPII ChIP-seq demonstrated that periportal but not pericentral hepatocytes display a basal (fed state) transcriptional activation of gluconeogenic genes that correlated with the basal level of gluconeogenic mRNA expression. Targeted single cell RNA-seq, HCR RNA-FISH, and PrimeFlow identified a subpopulation of periportal hepatocytes (approximately 10% of total hepatocytes) that simultaneously co-express both gluconeogenic and lipogenic genes in the fed state. These dual-positive hepatocytes identified in normal mouse livers are also present in human hepatocytes from humanized mouse livers. Spatial metabolic imaging coupled with stable isotope tracing analyses at the single cell level demonstrated that these individual hepatocytes simultaneously undergo both gluconeogenesis and de novo lipogenesis. Euglycemic-hyperinsulinemic clamps coupled with PrimeFlow analyses further demonstrated that this novel hepatocyte subpopulation is naturally insulin resistant. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were accompanied by an increase in the number of these dual-positive hepatocytes, suggesting a paradigm shift in our understanding of how the liver becomes insulin resistant. Taken together, these data demonstrate the existence of a unique, naturally insulin-resistant subset of mouse and human periportal hepatocytes that have the capacity to simultaneously undergo both gluconeogenesis and de novo lipogenesis.

2026-04-10 | GSE315776 | GEO

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