Predicting drug-induced liver injury with micro-patterned co-cultured IPSC-derived human hepatocytes
Researchers from Colorado State University used an enhanced process for creating human hepatocyte-like cells derived from induced pluripotent stem cells (iPSC-HH) to produce hepatocytes with a more consistent phenotype and longer life span than previous methods have yielded. In a new paper in Toxicological Sciences, the team describes the ability of these new cells to predict drug-induced liver injury.
The authors point out that primary human hepatocytes (PHH) are ideal for drug metabolism and toxicity-testing because of their long-term in vitro viability. But PHH availability is limited both in quantity and genetic diversity, and the cells exhibit considerable functional variability from lot to lot. Conventional IPSC-HHs have shown promise as an unlimited and customizable source of cells, but in previous culture attempts, cell functions decline very quickly in vitro, making IPSC-HHs most useful for acute toxicity studies of highly toxic substances, but not repeated-dose or metabolism studies.
The authors constructed a “micropatterned co-culture platform” (MPCC) by coating each well of a 96-well plate with collagen shaped by lithography to form “circular collagenous islands” to which IPSC-HHs could attach and grow. A previous paper showed that the resulting “iMPCCs” exhibited normal hepatocyte functions for up to four weeks (Berger et al., 2014). In the current paper, the authors compared iMPCCs to similarly co-cultured PHHs (PHH-MPCCs) and conventional iPSC-HHs, reporting that iMPCCs outperformed iPSC-HHs in classifying 47 hepatoxic and non-toxic drugs, and paralleled PHH-MPCCs. The iMPCCs also correctly ordered a group of 24 hepatoxins by relative toxicity.
Full citation of this paper: Ware, B.R., Berger, D.R., and Khetani, S.R. (2015). “Prediction of Drug-Induced Liver Injury in Micropatterned Co-cultures Containing iPSC-Derived Human Hepatocytes.” Toxicological Sciences: doi: 10.1093/toxsci/kfv048 [epub ahead of print]
Posted: May 27, 2015