Human Induced Pluripotent Stem Cell-Derived Hepatocyte-Like Cells as a Potential New Tool to Understand Small Molecule Kinase Inhibitors Induced Hepatotoxicity

摘要

Drug-induced liver injury (DILI) remains a persistent problem in medical practice and medical product development, complicated by the multiple mechanisms by which liver injury (hepatotoxicity) can be elicited as well as differences between species.1 Accordingly, several approaches using human cell-based in vitro models have been explored,1-2 ranging from cell lines derived from human hepatomas to donor-derived primary human hepatocytes.3 Over the last decade and a half the potential of deriving hepatocyte-like cells from human stem cells has been explored, to the extent that now human induced pluripotent stem cell-derived hepatocyte-like cells (HiPS-HLC) are routinely derived,45 and are being rapidly commercialized. At least five vendors are now available in the US, and some universities begin to provide contract services to help prepare HiPS-HLC starting from human blood samples. These cells possess some characteristics of primary cultured hepatocytes, the current gold standard for drug metabolism and toxicity study under in vitro conditions.367 However, detailed characterizations of HiPS-HLC are limited,78 and suggest that in general these cells do not reflect characteristics of primary hepatocytes freshly isolated from adult human livers. Nonetheless, a promising application of HiPS-HLC lies in the screening of compounds for hepatotoxicity,3'79 a bottleneck issue in drug discovery and development. A small number of drugs have been tested for this purpose with some success.7 This review will discuss the utility of HiPS-HLC in the study of small molecule kinase inhibitors (KIs) induced hepatotoxicity.