Gómez-Lechón María José, Tolosa Laia
Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe de Valencia, Torre A, 6ª Planta, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain.
CIBERehd, FIS, 08036, Barcelona, Spain.
Arch Toxicol. 2016 Sep;90(9):2049-2061. doi: 10.1007/s00204-016-1756-1. Epub 2016 Jun 20.
Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.
药物性肝损伤（DILI）是药物研发临床阶段和批准后阶段失败的常见原因，对制药行业构成了关键挑战。目前的动物模型对人类DILI的预测能力较差。尽管已经提出了几种基于人类细胞的模型用于检测人类DILI，但人类原代肝细胞仍然是临床前毒理学筛查的金标准。然而，其使用受到可用性有限、变异性和表型不稳定性的阻碍。相比之下，多能干细胞，包括胚胎干细胞和诱导多能干细胞（iPSC），在体外可大量增殖，并可通过添加可溶性因子分化为肝细胞。这为多种应用提供了稳定的肝细胞来源，包括早期临床前肝毒性筛查。此外，iPSC还有潜力从不同个体建立基因型特异性细胞，这将提高毒性试验的预测性，使临床试验更成功。因此，从多能干细胞衍生的人类肝细胞样细胞的产生似乎有望克服肝细胞制备的局限性，并有望在药物研发早期的临床前肝毒性风险评估中产生重大影响。
