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Directed induction of anterior and posterior primitive streak by Wnt from embryonic stem cells cultured in a chemically defined serum-free medium

Mio Nakanishi^*, Akira Kurisaki, Yohei Hayashi^*, Masaki Warashina, Shoichi Ishiura^*, Miho Kusuda-Furue^,|| and Makoto Asashima^1,*,,||

^* Department of Life Sciences (Biology), Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan;

Organ Development Research Laboratory, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan;

Genome Research Laboratories, Wako Pure Chemical Industries, Ltd., Hyogo, Japan;

Division of Bioresources, National Institute of Biomedical Innovation, Osaka, Japan; and

^|| International Cooperative Research Project (ICORP), Japan Science and Technology Agency, Tokyo, Japan

¹ Correspondence: Department of Life Sciences (Biology), Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan. E-mail: asashi{at}bio.c.u-tokyo.ac.jp

Formation of the primitive streak (PS) is the initial specification step that generates all the mesodermal and endodermal tissue lineages during early differentiation. Thus, a therapeutically compatible and efficient method for differentiation of the PS is crucial for regenerative medicine. In this study, we developed chemically defined serum-free culture conditions for the differentiation of embryonic stem (ES) cells into the PS-like cells. Cultures supplemented with Wnt showed induction of expression of a PS marker, the brachyury gene, followed by induction of the anterior PS markers goosecoid and foxa2, a posterior PS marker, evx1, and the endoderm marker sox17. Similar differentiation of PS by Wnt was also observed in human ES cells. Moreover, we revealed that the activation of the Wnt canonical pathway is essential for PS differentiation in mouse ES cells. These results demonstrated that Wnt is an essential and sufficient factor for the induction of the PS-like cells in vitro. These conditions of induction could constitute the initial step in generating therapeutically useful cells of the definitive endoderm lineage, such as hepatocytes and pancreatic endocrine cells, under chemically defined conditions.—Nakanishi, M., Kurisaki, A., Hayashi, Y., Warashina, M., Ishiura, S., Kusuda-Furue, M., Asashima, M. Directed induction of anterior and posterior primitive streak by Wnt from embryonic stem cells cultured in a chemically defined serum-free medium.

Key Words: mesendoderm • endoderm • regenerative medicine • brachyury • sox17