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Wilson’s disease model establishment from human induced pluripotent stem cells

宋, 丹 筑波大学 DOI:10.15068/0002005642

2022.11.24

概要

Induced pluripotent stem cells (iPSCs) is a promising tool to study path- physiological processes in vitro. My study was aiming to establish Wilson disease (WD) model with patients derived iPSC line. WD is a copper metabolic disorder, which is caused by defective ATP7B function. Copper chelators are used as the conventional therapies, which usually cause severe side effects and present significant variation in efficacy according to the cohort studies. Thus, exploring new therapeutic medicine for preventing aggravation to liver failure is urgent. Here, I used four iPSC lines generated from WD patients which are carrying compound heterozygous mutations on ATP7B. To establish the Wilson’s disease hepatic model, WD iPSCs were induced into hepatocyte with a robust differentiation protocol. WD disease features were further identified in WD- specific hepatocyte. Results showed that although the expression level of ATP7B protein was variable among different WD iPSC line derived hepatocytes, the expression and secretion of ceruloplasmin (Cp), which is a downstream copper carrier in plasma, were consistently decreased in WD-specific and ATP7B- deficient hepatocytes. ATP7B loss- and gain-of-functions were further manifested with ATP7B-deficient iPSCs and heterozygous-corrected R778L WD patient- derived iPSCs using CRISPR-Cas9-based gene editing. Cp secretion-based drug screening identified retinoids as promising candidates for rescuing Cp secretion. Furthermore, transcriptome analysis was performed to compare the global gene expression between the healthy donor iPSC derived hepatocytes and WD-specific hepatocytes. The transcriptome data was showing that the dysregulated genes in the WD-Hep was related to abnormalities of retinoid signaling pathway and lipid metabolism in WD-specific hepatocytes. To further evaluate the therapeutic value of all-trans retinoic acid (ATRA) on fatty liver related disease, I established the steatosis model with WD-specific hepatocyte. Results showed that ATRA could also alleviate reactive oxygen species (ROS) production induced by lipid accumulation in WD-specific hepatocytes treated with oleic acid. These patient-derived iPSC-based hepatic models provide effective platforms to develop potential therapeutics for hepatic steatosis in WD and other fatty liver diseases.

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