Abstract
Monkey embryonic stem (ES) cells have characteristics that are similar to human ES cells, and might be useful as a substitute model for preclinical research. When embryoid bodies (EBs) formed from monkey ES cells were cultured, expression of many hepatocyte-related genes including cytochrome P450 (Cyp) 3a and Cyp7a1 was observed. Hepatocytes were immunocytochemically observed using antibodies against albumin (ALB), cytokeratin-8/18, and α1-antitrypsin in the developing EBs. The in vitro differentiation potential of monkey ES cells into the hepatic lineage prompted us to examine the transplantability of monkey EB cells. As an initial approach to assess the repopulation potential, we transplanted EB cells into immunodeficient urokinase-type plasminogen activator transgenic mice that undergo liver failure. After transplantation, the hepatocyte colonies expressing monkey ALB were observed in the mouse liver. Fluorescence in-situ hybridization revealed that the repopulating hepatocytes arise from cell fusion between transplanted monkey EB cells and recipient mouse hepatocytes. In contrast, neither cell fusion nor repopulation of hepatocytes was observed in the recipient liver after undifferentiated ES cell transplantation. These results indicate that the differentiated cells in developing monkey EBs, but not contaminating ES cells, generate functional hepatocytes by cell fusion with recipient mouse hepatocytes, and repopulate injured mouse liver.
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Acknowledgments
We thank F. Ono (Laboratory Primates, Tsukuba) for providing cynomolgus liver tissues and T. Irie, S. Kakinuma, Y. Kumashiro (Tokyo Medical and Dental University), Y. Kageyama, H. Kono, and Y. Yoshizane (Yoshizato Project, CLUSTER, Hiroshima) for their advice and helpful discussion. This work was supported by Grants-in-Aid for Scientific Research (13470232, 15659067, 16390357, 17770051) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Atsuko Ohuchi Memorial Research Fund for Medical Research.
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Okamura, K., Asahina, K., Fujimori, H. et al. Generation of hybrid hepatocytes by cell fusion from monkey embryoid body cells in the injured mouse liver. Histochem Cell Biol 125, 247–257 (2006). https://doi.org/10.1007/s00418-005-0065-1
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DOI: https://doi.org/10.1007/s00418-005-0065-1