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EMBRYONIC STEM CELLS

Improved Safety of Hematopoietic Transplantation with Monkey Embryonic Stem Cells in the Allogeneic Setting

^a Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan;
^b Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan;
^c Department of Veterinary Pathology, Nippon Veterinary and Animal Science University, Tokyo, Japan;
^d Department of Neurology, Jichi Medical University, Tochigi, Japan;
^e Departments of Obstetrics and Gynecology and
^f Surgery, National Center for Child Hearth and Development, Tokyo, Japan

Key Words. Cynomolgus monkey • Hematopoiesis • Embryonic stem cell • In utero transplantation • Teratoma • Purging • Tumor prevention

Correspondence: Yutaka Hanazono, M.D., Ph.D., Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Telephone: +81-285-58-7450; Fax: +81-285-44-5205; e-mail: hanazono{at}jichi.ac.jp

Received August 13, 2005; accepted for publication January 23, 2006.

Cynomolgus monkey embryonic stem cell (cyESC)-derived in vivo hematopoiesis was examined in an allogeneic transplantation model. cyESCs were induced to differentiate into the putative hematopoietic precursors in vitro, and the cells were transplanted into the fetal cynomolgus liver at approximately the end of the first trimester (n = 3). Although cyESC-derived hematopoietic colony-forming cells were detected in the newborns (4.1%–4.7%), a teratoma developed in all newborns. The risk of tumor formation was high in this allogeneic transplantation model, given that tumors were hardly observed in immunodeficient mice or fetal sheep that had been xeno-transplanted with the same cyESC derivatives. It turned out that the cyESC-derived donor cells included a residual undifferentiated fraction positive for stage-specific embryonic antigen (SSEA)-4 (38.2% ± 10.3%) despite the rigorous differentiation culture. When an SSEA-4-negative fraction was transplanted (n = 6), the teratoma was no longer observed, whereas the cyESC-derived hematopoietic engraftment was unperturbed (2.3%–5.0%). SSEA-4 is therefore a clinically relevant pluripotency marker of primate embryonic stem cells (ESCs). Purging pluripotent cells with this surface marker would be a promising method of producing clinical progenitor cell preparations using human ESCs.

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