Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening

Abstract

Hepatotoxicity is an enormous and increasing problem for the pharmaceutical industry. Early detection of problems during the drug discovery pathway is advantageous to minimize costs and improve patient safety. However, current cellular models are sub-optimal. This review addresses the potential use of pluripotent stem cells in the generation of hepatic cell lineages. It begins by highlighting the scale of the problem faced by the pharmaceutical industry, the precise nature of drug-induced liver injury and where in the drug discovery pathway the need for additional cell models arises. Current research is discussed, mainly for generating hepatocyte-like cells rather than other liver cell-types. In addition, an effort is made to identify where some of the major barriers remain in translating what is currently hypothesis-driven laboratory research into meaningful platform technologies for the pharmaceutical industry.

Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy

“…Specifically, iPSC-hepatocytes generated from individuals with different P450 polymorphisms would be of great value for drug metabolism study and toxicity prediction of new drugs (Asgari et al, 2010). Moreover, the utilizing of iPSC would offer opportunities to generate liver cells at different stages of maturation, as well as the potential to give rise to all the composite cells of the adult liver, which may provide extra advantages and substantially expand the scope of the traditional drug metabolism and toxicology studies (Baxter et al, 2010).…”

“…In vitro hepatocyte models have innate limitations in terms of preserving metabolic enzyme activities and maturity. In addition, despite of numerous protocols aiming at efficient differentiation of hepatocytes from human pluripotent stem cells, phenotypic stability and expansion capacity of derived hepatocytes are still major challenges for the application, as the cell purity and scale-up capability are both mandatory for practical use in pharmaceutical industry (Baxter et al, 2010). Even if the direct in vitro application of iPSC-hepatocytes in drug discovery is still in infant stage, a feasible alternative would be an in vivo, artificial human liver for drug testing (Yoshizato and Tateno, 2009).…”

Human Pluripotent Stem Cells and Drug Discovery: A New Beginning

“…Combinations of growth factors and signal activators [53][54][55][56][57][58][59][60][61] , co-culture techniques [62][63][64] and various matrices [65][66][67] have been implemented in attempts to induce hepatic differentiation. Once generated, hPSC-hepatocytes are reported to exhibit metabolic functionality such as glycogen storage, albumin secretion, urea synthesis, uptake and release of indocyanine green, AAT secretion and LDL uptake 53,57,[67][68][69] . Regardless of their metabolic functionalities, the most critical aspect for potential application of hPSChepatocytes in safety pharmacology and toxicology is their ability to metabolize drugs using phase I and II enzymes which facilitate drug metabolism .…”

Stem Cells and Stem Cell-derived Tissues and Their Use in Safety Assessment

“…Primary cultured hepatocytes, the current gold standard for in vitro liver-based questions, are an integral part of early safety assays, including generic cellular toxicity signals, metabolic drug activation, P450 induction signals, transporter activity, formation of toxic drug metabolites, and impairment of mitochondrial function, to name just a few. Parenchymal hepatocytes are the major cell type of the liver and, when cultured, can retain many physiological functions of intact liver, albeit only for a limited time, and exhibit cytochrome P450 levels that vary greatly from preparation to preparation (53). Consequently, there is a strong need for a human-specific in vitro test system that mirrors the critical characteristics of the liver, and extensive efforts are being directed toward the establishment of hPSC-derived hepatocytes.…”