Michelle Stevens, Fuhrken, P., Kannemeier, C., Luebke-Wheeler, J., Swanson, B.J., Wang, W., Ott, V.L., Nuwaysir, E.
Cellular Dynamics International, Inc., Madison, WI USA
Liver toxicity and alterations of hepatic physiology are the most frequently occurring reasons for pre-clinical failure of drugs in development and market withdrawal of approved drugs. Liver diseases associated with drug toxicity can be attributed, in large part, to the lack of biologically relevant and predictive model systems. Current hepatocyte model systems include primary human hepatocytes (PHH) harvested from cadavers, immortalized cell lines and animal models. Each of these presents limitations in functionality, reproducibility and/or availability. Human hepatocytes derived from induced pluripotent stem cells (iPSCs), which are stem cells derived from adult tissue, offer the potential to overcome these limitations. In addition, recent studies have demonstrated that iPSC-derived hepatocytes generated from individuals with various liver diseases can be used for in vitro disease modeling and drug screening. We have developed human iPSC-derived hepatocytes that are >95% pure and exhibit characteristic hepatocyte morphology, gene and protein expression (e.g. albumin, alpha-1-antitrypsin, ASGR1, HNF family transcription factors). Human iPSC-derived hepatocytes produce albumin protein at levels similar to PHH and ~7-fold greater than HepG2 cells. In addition, ³50% of the cells store glycogen and lipid, as demonstrated by Periodic Acid Schiff and Oil Red staining, respectively. Human iPSC-derived hepatocytes express Phase I and II metabolic enzymes (e.g. CYP1A2, 2B6, 2C8/9/19, 2D6, 3A4, UGT, ST and GST) at levels similar to PHH, and exhibit ≥3-fold induction of CYP3A4. Finally, human iPSC-derived hepatocytes express key uptake and efflux transporters (e.g. MDR-1/P-gp, MRP2, BSEP, BCRP, NTCP and OATPs) and form functional bile canaliculi. The development of human iPSC-derived hepatocotyes that recapitulate in vivo hepatocyte function will enable new strategies for disease modeling and drug discovery, better predictivity of drug-induced hepatotoxicity, and the delivery of new drug therapies across a wide range of diseases.
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