TY - JOUR
T1 - Differentiation and Transplantation of Human Embryonic Stem Cell-Derived Hepatocytes
AU - Basma, Hesham
AU - Soto-Gutiérrez, Alejandro
AU - Yannam, Govardhana Rao
AU - Liu, Liping
AU - Ito, Ryotaro
AU - Yamamoto, Toshiyuki
AU - Ellis, Ewa
AU - Carson, Steven D.
AU - Sato, Shintaro
AU - Chen, Yong
AU - Muirhead, David
AU - Navarro-Álvarez, Nalu
AU - Wong, Ronald J.
AU - Roy-Chowdhury, Jayanta
AU - Platt, Jeffrey L.
AU - Mercer, David F.
AU - Miller, John D.
AU - Strom, Stephen C.
AU - Kobayashi, Naoya
AU - Fox, Ira J.
N1 - Funding Information:
Funding The authors disclose the following: Supported by a Grant-in-Aid for Scientific Research (B) of the Japan Society for the Promotion of Science (to N.K.), National Institutes of Health grants DK-7-0004 (to S.C.S), HL52297 (to J.L.P.), DK 067440 (to J.R.–C.), and DK48794 and AI49472 (to I.J.F.).
PY - 2009/3
Y1 - 2009/3
N2 - 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.
AB - 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.
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U2 - 10.1053/j.gastro.2008.10.047
DO - 10.1053/j.gastro.2008.10.047
M3 - Article
C2 - 19026649
AN - SCOPUS:60449098836
SN - 0016-5085
VL - 136
SP - 990-999.e4
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -