Highly Efficient Generation of Human Hepatocyte–Like Cells... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Highly Efficient Generation of Human Hepatocyte–Like Cells From Induced Pluripotent Stem Cells

Si-Tayeb, Karim1,*; Noto, Fallon K.1,*; Nagaoka, Masato1; Li, Jixuan1; Battle, Michele A.1; Duris, Christine2; North, Paula E.2; Dalton, Stephen3; Duncan, Stephen A.1,†

1_Department of Cell Biology, Neurobiology and Anatomy, Division of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI_

2_Department of Pathology, Division of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI_

3_Paul D. Coverdell Center for Biomedical and Health Sciences, University of Georgia, Athens, GA_

†Address reprint requests to: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. Email:[email protected]; fax: 414-456-6517.

Received 10 August 2009; Accepted 17 September 2009

Published online 1 October 2009 in Wiley InterScience (www.interscience.wiley.com).

Supported by National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases/National Heart, Lung and Blood Institute [NHLBI]) grants to S.A.D. and S.D. (National Institute for Child Health and Human Development/NHLBI), Advancing a Healthier Wisconsin Fund, as well as gifts from the Marcus Family, Phoebe R. and John D. Lewis Foundation, the Sophia Wolf Quadracci Memorial Fund, and the Dr. James Guhl Memorial Fund.

Potential conflict of interest: Nothing to report.

*These authors contributed equally to the manuscript.

Additional Supporting Information may be found in the online version of this article.

Abstract

There exists a worldwide shortage of donor livers available for orthotropic liver transplantation and hepatocyte transplantation therapies. In addition to their therapeutic potential, primary human hepatocytes facilitate the study of molecular and genetic aspects of human hepatic disease and development and provide a platform for drug toxicity screens and identification of novel pharmaceuticals with potential to treat a wide array of metabolic diseases. The demand for human hepatocytes, therefore, heavily outweighs their availability. As an alternative to using donor livers as a source of primary hepatocytes, we explored the possibility of generating patient-specific human hepatocytes from induced pluripotent stem (iPS) cells. Conclusion: We demonstrate that mouse iPS cells retain full potential for fetal liver development and describe a procedure that facilitates the efficient generation of highly differentiated human hepatocyte-like cells from iPS cells that display key liver functions and can integrate into the hepatic parenchyma in vivo . (Hepatology 2010.)