功能性肝细胞模型用于新药肝脏代谢分布研究

Transporter-mediated drug-drug interaction (DDI) study is one of the most important components for drug discovery and development. The latest released DDI guidance of FDA (2012) confirmed this concept for the first time. Primary hepatocyte is the gold standard of the transporter related DDI in liver; however, the price and complexity of primary hepatocytes culture limited its application in industry. The cell line generated by gene transfection technique, which may cause false positive results, is hard to investigate multiple transporter functions simultaneously. Our group is planning to combine transporter polarization regulation pathways with the direct reprogramming technique, generate mouse and human hepatocytes-like cells for drug PK and safty study (ADMET) in early drug discovery phase. The novel cell line is unlimited division, and has multiple transporters polarized expression. We will determine the major transporter polarization and characterize related pathway regulation mechanisms. This study will not only supply a powerful source as substitute for the primary hepatocytes in pharmaceutical industry, but also provide insights into the molecular nature of hepatocyte differentiation and potential therapies for liver diseases.

药物和体内药物转运体的相互作用是新药研发的重要组成部分，也是2012年FDA在指导原则中首次确认的新药评价原则。但是，用于这一研究的"金标准"原代肝细胞培养由于技术复杂，价格昂贵无法在工业界推广使用。细胞转染技术生产的细胞株由于可能引起假阳性结果也限制了它的应用，而且细胞转染无法同时考察多种不同转运体对于药物的影响。 本课题组决定利用药物转运体极化调控通路激活手段结合直接转分化技术，将从小鼠和人的体细胞直接产生的诱导样肝细胞转变为可以无限分化，具有多重药物转运体极化表达的细胞系，用于早期新药药代特征和安全性评价（ADMET）研究。同时，发掘类肝细胞重要药物转运体表达和代谢特征的调控机制。这一工作不仅对于制药行业意义重大，也为肝细胞分化机制研究和人源诱导样肝细胞在医学领域的进一步应用打下良好基础。

本课题组利用药物转运体极化调控通路激活、小分子诱导等手段，将从小鼠和人的体细胞直接产生的诱导样肝细胞分别转变为可以无限分化，具有多重药物转运体极化表达的细胞系，在对这两种细胞系进行特征评价并与原代小鼠、人肝细胞进行比较之后，成功用于早期新药药代特征和安全性评价研究，使利用肝样细胞替代昂贵的原代肝细胞成为可能。同时，利用现有模型，发掘类肝细胞重要药物转运体表达和代谢特征的调控机制，对于胆汁淤积性药物肝损伤的研究有了深入进展。本课题的研究成果为肝细胞分化机制研究和人源诱导样肝细胞在医学领域的进一步应用打下良好基础，并在制药行业产生良好应用前景。