Differentiation and Transplantation of Human Embryonic Stem Cell-Derived Hepatocytes

Hesham Basma, Alejandro Soto-Gutiérrez, Govardhana Rao Yannam, Liping Liu, Ryotaro Ito, Toshiyuki Yamamoto, Ewa Ellis, Steven D. Carson, Shintaro Sato, Yong Chen, David Muirhead, Nalu Navarro-Álvarez, Ronald J. Wong, Jayanta Roy-Chowdhury, Jeffrey L. Platt, David F. Mercer, John D. Miller, Stephen C. Strom, Naoya Kobayashi, Ira J. Fox

Research output: Contribution to journalArticlepeer-review

386 Scopus citations

Abstract

Background & Aims: The ability to obtain unlimited numbers of human hepatocytes would improve the development of cell-based therapies for liver diseases, facilitate the study of liver biology, and improve the early stages of drug discovery. Embryonic stem cells are pluripotent, potentially can differentiate into any cell type, and therefore could be developed as a source of human hepatocytes. Methods: To generate human hepatocytes, human embryonic stem cells were differentiated by sequential culture in fibroblast growth factor 2 and human activin-A, hepatocyte growth factor, and dexamethasone. Functional hepatocytes were isolated by sorting for surface asialoglycoprotein-receptor expression. Characterization was performed by real-time polymerase chain reaction, immunohistochemistry, immunoblot, functional assays, and transplantation. Results: Embryonic stem cell-derived hepatocytes expressed liver-specific genes, but not genes representing other lineages, secreted functional human liver-specific proteins similar to those of primary human hepatocytes, and showed human hepatocyte cytochrome P450 metabolic activity. Serum from rodents given injections of embryonic stem cell-derived hepatocytes contained significant amounts of human albumin and α1-antitrypsin. Colonies of cytokeratin-18 and human albumin-expressing cells were present in the livers of recipient animals. Conclusions: Human embryonic stem cells can be differentiated into cells with many characteristics of primary human hepatocytes. Hepatocyte-like cells can be enriched and recovered based on asialoglycoprotein-receptor expression and potentially could be used in drug discovery research and developed as therapeutics.

Original languageEnglish (US)
Pages (from-to)990-999.e4
JournalGastroenterology
Volume136
Issue number3
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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