Transplantation of Embryonic Stem Cell-derived Endodermal Cells Into Mice with Induced Lethal Liver Damage

¹ From Department of Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan, Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
² From Department of Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan
³ Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
⁴ Department of Development and Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
⁵ Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Nara, Japan.

^* To whom correspondence should be addressed. E-mail: ikai{at}kuhp.kyoto-u.ac.jp.

	Abstract

Embryonic stem cells (ESCs) are a potential cell source for cell therapy. However, there is no evidence that cell transplantation using ESC-derived hepatocytes is therapeutically effective. The main objective of this study was to assess the therapeutic efficacy of the transplantation of ESC-derived endodermal cells into a liver injury model. The -galactosidase-labeled mouse ESCs were differentiated into alpha-fetoprotein (AFP)-producing endodermal cells. AFP-producing cells or ESCs were transplanted into transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/promoter. Selective damage was induced in the recipient hepatocytes by the administration of DT. Although the transplanted AFP-producing cells had repopulated only 3.4% of the total liver mass seven days after cell transplantation, they replaced 32.8% of the liver by day 35. However, these engrafted cells decreased (18.3% at day 40 and 7.9% at day 50) after the cessation of DT administration, and few donor cells were observed by days 60 to 90. The survival rate of the AFP-producing cell-transplanted group (66.7%) was significantly higher in comparison to that of the sham-operated group (17.6%). No tumors were detected by day 50 in the AFP-producing cell-transplanted group; however, splenic teratomas did form 60 days or later after transplantation. ESC transplantation had no effect on survival rates; furthermore, there was a high frequency of tumors in the ESC-transplanted group 35 days after transplantation. In conclusion, this study demonstrates, for the first time, that ESC-derived endodermal cells improve the survival rates after transplantation into mice with induced hepatocellular injury.

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