Transcriptomal profiling of liver microphysiological system (MPS) co-culture NASH model under varying culture conditions
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ABSTRACT:
PROVIDER: PRJNA706750 | ENA |
REPOSITORIES: ENA
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Project description:Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with the standard in vitro assays. Here, we connect models of key metabolic organs, pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modelling, we show that hyperglycemia and high cortisone induce glucose dysregulation in the pancreas-liver microphysiological system (MPS) mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. In turn, a physiological culture condition maintains the glucose tolerance and beta cell function. This method was evaluated for reproducibility in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins as demonstrated with a combined transcriptome and proteome analysis.
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Project description:Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with the standard in vitro assays. Here, we connect models of key metabolic organs, pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based preclinical system. Aided by mechanistic mathematical modelling, we show that hyperglycemia and high cortisone induce glucose dysregulation in the pancreas-liver microphysiological system (MPS) mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. In turn, a physiological culture condition rescues the glucose tolerance and beta cell function. This method was evaluated for repeatability in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic targets as demonstrated with a combined transcriptome and proteome analysis.
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Project description:Ochratoxin A (OTA) is one of the most abundant mycotoxin contaminants in food stuffs and possesses carcinogenic, nephrotoxic, teratogenic and immunotoxic properties. Especially, severe nephrotoxicity is of great concern, as characterized by degeneration of epithelial cells of the proximal tubules and interstitial fibrosis. However, its mechanism of toxicity, hazard identification as well as genetic risk factors contributing to OTA toxicity in humans has been elusive due to the lack of adequate models that fully recapitulate kidney function in vitro. The present study attempts to evaluate dose-response relationships, identify the contribution of active transport proteins that govern renal disposition of OTA, and determine the role of metabolism in bioactivation and detoxification of OTA using a 3D human kidney proximal tubule microphysiological system (kidney MPS). We demonstrated that IC50 values of OTA in kidney MPS culture (0.375 – 1.21 µM) were in good agreement with clinical toxic concentrations of OTA in urine. Surprisingly, no enhancement of kidney injury biomarkers was evident in the effluents of kidney MPS after OTA exposure despite significant toxicity observed by LIVE/DEAD staining, rather these biomarkers were decreased in OTA concentration-dependent manner. Furthermore, the effect of 1-aminobenzotriazole (ABT) and 6-(NBD-4-ylthio-) hexanol (NBDHEX), pan-inhibitor of P450 and GST enzymes, respectively, on the OTA-induced toxicity in kidney MPS was examined, which resulted in significant enhancement of OTA-induced toxicity by NBDHEX (3 µM) treatment whereas ABT (1 mM) treatment decreased OTA-induced toxicity, suggesting the roles of GSTs and P450 enzymes in the detoxification and bioactivation of OTA, respectively. Additionally, OTA transport studies using kidney MPS in the presence and absence of inhibitor of organic anion transporter(s), probenecid (1 mM), revealed the role of organic anionic membrane transporter(s) in the kidney specific disposition of OTA. Our findings provide a better understanding of the mechanism of OTA-induced kidney injury which may support changes in risk assessment, regulatory agency policies on allowable exposure levels and determination of genetic factors in high-risk populations against OTA nephrotoxicity.
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Project description:to compare the incremental advances that each cell type brings to the phenotype of the others in the glomerulus we compared TGCs (triculture), BGCs (co-culture), and plate cultures (monocultures) The function of the glomerulus depends on complex cell-cell/matrix interactions and replication of this in vitro would aid biological understanding in both health and disease. Previous models have not fully reflected all cell types and interactions present. We report here the development of a microphysiological system which contains all resident renal cell types in an anatomically relevant manner. We demonstrate functionally appropriate retention of albumin in the system along with providing a detailed transcriptomic analysis of the contributing biology of each cell type. The important role of mesangial cells is shown in promoting the health and maturity of the other cell types. AdditionallyAdditionally, we demonstrate that glomerular cells in simple 2D culture exhibit a state more reflective of human disease than previously recognised. This in vitro model will expand our capability to investigate glomerular biology in a more translatable manner by the inclusion of the important mesangial cell compartment.
2023-12-31 | GSE211517 | GEO
Project description:Chronic white adipose tissue (WAT) inflammation has been recognized as a critical early event in the pathogenesis of obesity-related disorders. This process is characterized by the increased residency of proinflammatory M1 macrophages in WAT. However, the lack of an isogenic human macrophage-adipocyte model has limited biological studies and drug discovery efforts, highlighting the need for human stem cell-based approaches. Here, human induced pluripotent stem cell (iPSC) derived macrophages (iMACs) and adipocytes (iADIPOs) are cocultured in a microphysiological system (MPS). iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown-like structures (CLSs)-like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity. Significantly more CLS-like morphologies formed in aged and palmitic acid-treated iMAC-iADIPO-MPS, showing the ability to mimic inflammatory severity. Importantly, M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs. Both RNAseq and cytokines analyses revealed a reciprocal proinflammatory loop in the interactions of M1 iMACs and iADIPOs. Our iMAC-iADIPO-MPS thus successfully recreates pathological conditions of chronically inflamed human WAT, allowing us to study the dynamic inflammatory progression and identify clinically relevant therapies.
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Project description:Mucopolysaccharidosis VII (MPS VII) is due to mutations within the gene encoding the lysosomal enzyme beta-glucuronidase, and results in the accumulation of glycosaminoglycans. MPS VII causes aortic dilatation and elastin fragmentation. In this study we performed microarray analysis of ascending aortas from normal and MPS VII mice, trying to find out possible genes responsible for the phenotype observed. In addition, during our breeding strategy, we noticed that some MPS VII mice had less dilated aortas, and we proposed that an yet-unidentified gene could be responsible for the difference observed. We therefore included in the analysis two MPS VII mice with aortas that were not dilated. Total RNA extracted from ascending aortas from 3 Normal mice, 3 MPS VII mice with dilated aortas and 2 MPS VII mice with aortas that were not dilated.
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