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干细胞疾病模型在肝脏代谢疾病研究和药物研发中的应用

吴晓珊, 李爽, 丁秋蓉^*

华东理工大学药学院，上海 200237；中国科学院上海营养与健康研究所，上海 200031

摘要

新药研发的失败率之高众所周知，其中一个原因是依靠动物实验获得的临床前数据无法真实反映人类生理情况，不可避免地在药物进入临床试验后产生偏差，最终可能导致研发失利。基于人诱导性多能干细胞(induced pluripotent stem cells, iPSCs)或成体干细胞建立的疾病模型一方面提供了大量的细胞原材料；另一方面，由于iPSCs或成体干细胞可来源于患者，因而可准确模拟疾病的遗传背景。因此，干细胞疾病模型为药物临床前试验提供了更贴近人体生理和病理情况的体外细胞模型。更进一步地，通过建立群体iPSCs细胞库，可在体外细胞培养皿内进行人类遗传学研究，采用全基因组关联研究(genome-wide association study, GWAS)及定量性状基因座(quantitative trait locus, QTL)等方法筛选人群中与疾病、药物敏感性差异、细胞毒性差异相关的易感位点，为特定药物的毒性、易感性人群间差异等提供遗传学基础，进而为后续临床试验中合适的试验人群的招募提供理论依据。因而，干细胞疾病模型可潜在辅助新药研发，提高新药临床前试验的准确率，降低新药研发的周期和成本。本文以肝脏代谢疾病为对象，对干细胞来源的肝脏细胞疾病模型在代谢功能方面的生理机制研究、药物筛选和评估等领域进行综述。

关键词： 人多能干细胞; 人肝细胞样细胞; 体外肝脏群体队列; 3D类器官; 全基因组关联研究; 定量性状基因座

分类号：Q485;R333.4

Applications of stem cell disease models in liver metabolic research and drug development

WU Xiao-Shan, LI Shuang, DING Qiu-Rong^*

School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China；Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China

Abstract

The high failure rate of the new drug development has been well recognized. Relying on the pre-clinical data obtained from animal experiments will inevitably cause a low concordance with human clinical trials, which will eventually lead to new drug development failure. Employing human induced pluripotent stem cells (iPSCs) or adult stem cells to simulate disease models can not only provide an unlimited cell materials, but also faithfully represent the genetic background of a certain disease, when iPSCs or adult stem cells derived from patients with a specific disease genetic variation are applied. In addition, gene editing methods can be used to introduce genetic variants of interest into stem cells to generate disease models. Furthermore, by establishing a cell bank with a population of iPSCs in petri dish, in vitro human genetic studies can be carried out in these cells, with GWAS and QTL studies applied to identify genetic variants that are associated with drug sensitivity or cytotoxicity. These efforts may offer valuable information for the recruitment of suitable patients for clinical trials. Therefore, stem cell-derived disease models can provide valuable resources for the pathophysiological studies of diseases as well as the drug development. In this review, we will briefly introduce the development of the liver disease models derived from stem cells and their applications in disease study and drug development.  

Key words: iPSC; hepatocyte-like cells; in vitro human liver population cohorts; 3D organoid; genome-wide association studies (GWAS); quantitative trait locus (QTL)

收稿日期：2020-11-17　　录用日期：2021-03-11

通讯作者：丁秋蓉　　E-mail: qrding@sibs.ac.cn

DOI: 10.13294/j.aps.2021.006

引用本文：

吴晓珊, 李爽, 丁秋蓉. 干细胞疾病模型在肝脏代谢疾病研究和药物研发中的应用[J]. 生理学报 2021; 73 (5): 694-706.

WU Xiao-Shan, LI Shuang, DING Qiu-Rong. Applications of stem cell disease models in liver metabolic research and drug development. Acta Physiol Sin 2021; 73 (5): 694-706 (in Chinese with English abstract).