Liver Extracellular Matrices Bioactivated Hepatic Spheroids as a Model System for Drug Hepatotoxicity Evaluations
Liver Extracellular Matrices Bioactivated Hepatic Spheroids as a Model System for Drug Hepatotoxicity Evaluations
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肝细胞外基质生物活化肝球体作为药物肝毒性评估的模型系统
DOI：
10.1002/adbi.201800110
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发表时间：
2018-10-01
影响因子：
4.1
通讯作者：
Wang, Yunfang
中科院分区：
文献类型：
--
作者：
Liu, Juan;Li, Ruihong;Wang, Yunfang
药物性肝损伤(DILI)是导致急性肝功能衰竭的主要原因。预测或评估DILI的一个主要障碍是缺乏一个实验模型(S)来概括稳定和生理相关的肝功能，并准确反映药物的肝毒性水平。天然的细胞外基质是由常驻细胞分泌和维持的，作为细胞培养和细胞输送的生物材料受到了极大的关注。在这项研究中，建立了一个肝脏球体模型系统，用冷冻粉碎的肝脏生物基质支架(LBSS)处理，用于DILI的研究。LBS提供了与体内相似的肝脏特异性代谢特征的生物激活微环境，导致LBS生物激活模型系统显示出增强肝脏特异性功能(白蛋白分泌、尿素合成、糖原储存)、细胞色素P450酶(Cyps)代谢活性、胆汁排泄以及I、II期代谢酶、转运蛋白和核受体表达增加的事实，这些共同假设是由于细胞-细胞和细胞-基质相互作用增加所致。用LBS激活的肝球体进行毒性评估显示，在识别肝毒性化合物方面提高了敏感性。综上所述，利用该模型系统，开发了一种简单但健壮的高通量兼容方法，该方法在毒性筛选分析中显示出巨大的潜力，并代表了一种研究DILI的动物模型的替代方案。
Drug-induced liver injury (DILI) is a leading cause of acute liver failure. A major obstacle in the prediction or evaluation of DILI is the lack of an experimental model(s) that recapitulates the stable and physiologically relevant liver functions and reflects accurately the level of drug hepatotoxicity. Native extracellular matrices that are secreted and maintained by resident cells are receiving great interest as biomaterials for cell culture and cell delivery. In this study, a hepatic spheroid model system, treated with cryopulverized liver biomatrix scaffolds (LBSs), is established for DILI investigations. The LBSs provide a liver-specific microenvironment bioactivating metabolic traits paralleling those in vivo, resulting in the fact that LBS-bioactivated model system shows enhancing liver-specific functions (albumin secretion, urea synthesis, glycogen storage), cytochrome P450 enzymes (CYPs) metabolic activity, bile excretion, and increased expression of phase I and II metabolism enzymes, transporters, and nuclear receptors, collectively hypothesized to result from increased cell-cell and cell-matrix interactions. Toxicity assessments with LBS-bioactivated hepatic spheroids reveal an improved sensitivity in identifying hepatotoxic compounds. In summary, using this model system, a simple but robust high-throughput-compatible methodology is developed, which shows great potential for use in toxicity screening assays, and represents an alternative to animal models for studying DILI.