Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin, and alpha-fetoprotein, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and CYP3A4 metabolism, which is essential for drug and toxicology testing. Conclusion: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSCs that exhibits key attributes of

hepatocytes, and the DMXAA potential application of iPSC-derived HE in studying human liver biology. In particular, iPSCs from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionize predictive drug toxicology assays and allow the creation of in vitro hepatic disease models. (HEPATOLOGY 2009.) Human induced pluripotent stem cells (iPSCs) are reprogrammed mature somatic fibroblasts which represent a pluripotent cell population able to generate all primary cell types in vitro.1–3 The ability to derive iPSCs from an indefinite range of genotypes makes them an attractive resource on which to model liver function reflecting the complexity of polygenic influences on metabolism in vitro. Another BIBW2992 in vivo facet of iPSC technology

is the ability to study the impact of gene polymorphisms in a native chromatin setting and model gene interactions with precision. Therefore iPSC-derived models hold great potential to develop a detailed understanding of human liver disease and metabolism including drug toxicity (for a review, see Dalgetty et al.4). Any methods which might streamline and standardize the process of drug and toxicology testing, which currently relies on primary human hepatocytes (PHHs), would represent a significant development. Therefore, an iPSC resource representative of polymorphic Mannose-binding protein-associated serine protease variants and ethnic groups, unhindered by quality and supply, would revolutionize predictive drug toxicology assays and

have an effect on drug attrition. Presently, PHHs are the gold standard cell type used in predictive drug toxicology. Unfortunately, PHHs are a scarce, heterogeneous, and expensive resource which function only short-term in vitro. The generation of hepatic endoderm (HE) from iPSCs has the potential to fulfill the major challenge to acquire the reliable and clonal source of functional human hepatocyte cells for biotechnology purposes. To date, efficient models of deriving HE from iPSCs have not been described or developed. Capitalizing on our recent investigations that human embryonic stem cells (hESCs) can be stimulated to form HE,5 we have developed a parallel methodology for iPSCs; here, we describe the generation of functional HE from multiple human iPSC lines that can potentially model human drug metabolism.