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Human iPSC-derived proinflammatory macrophages cause insulin resistance in an isogenic white adipose tissue microphysiological system

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228094 | GEO | 2023/03/28

REPOSITORIES: GEO

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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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Human iPSC-derived proinflammatory macrophages cause insulin resistance in an isogenic white adipose tissue microphysiological system

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