Heparan sulfate regulates self-renewal and pluripotency of embryonic stem cells.
Embryonic stem (ES) cell self-renewal and pluripotency are maintained by several signaling cascades and by expression of intrinsic factors, such as Oct3/4 and Nanog. The signaling cascades are activated by extrinsic factors, such as leukemia inhibitory factor, bone morphogenic protein, and Wnt. However, the mechanism that regulates extrinsic signaling in ES cells is unknown. Heparan sulfate (HS) chains are ubiquitously present as the cell surface proteoglycans and are known to play crucial roles in regulating several signaling pathways. Here we investigated whether HS chains on ES cells are involved in regulating signaling pathways that are important for the maintenance of ES cells. RNA interference-mediated knockdown of HS chain elongation inhibited mouse ES cell self-renewal and induced spontaneous differentiation of the cells into extraembryonic endoderm. Furthermore, autocrine/paracrine Wnt/beta-catenin signaling through HS chains was found to be required for the regulation of Nanog expression. We propose that HS chains are important for the extrinsic signaling required for mouse ES cell self-renewal and pluripotency.
Sasaki
Norihiko
N
Laboratory of Cell Biology, Department of Bioinformatics, Faculty of Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577; Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Hon-cho, Kawaguchi, Saitama 332-0012, Japan.
Okishio
Kazuhiko
K
Laboratory of Cell Biology, Department of Bioinformatics, Faculty of Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577.
Ui-Tei
Kumiko
K
Department of Biophysics and Biochemistry, Graduate School of Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Saigo
Kaoru
K
Department of Biophysics and Biochemistry, Graduate School of Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Kinoshita-Toyoda
Akiko
A
Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Hon-cho, Kawaguchi, Saitama 332-0012, Japan; Department of Bioanalytical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522.
Toyoda
Hidenao
H
Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Hon-cho, Kawaguchi, Saitama 332-0012, Japan; Department of Bioanalytical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522.
Nishimura
Tomoaki
T
Department of Nanostructure and Advanced Materials, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Kohrimoto, Kagoshima 890-0065; Sudx-Biotec Corporation, KIBC 461, 5-5-2, Minatojima-minami, Chuo-ku, Kobe 650-0047.
Suda
Yasuo
Y
Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Hon-cho, Kawaguchi, Saitama 332-0012, Japan; Department of Nanostructure and Advanced Materials, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Kohrimoto, Kagoshima 890-0065; Sudx-Biotec Corporation, KIBC 461, 5-5-2, Minatojima-minami, Chuo-ku, Kobe 650-0047.
Hayasaka
Michiko
M
Laboratory of Molecular Embryology, Department of Bioscience, Kitasato University School of Science, 1-15-1 Kitasato, Sagamihara, Kanagawa 228.
Hanaoka
Kazunari
K
Laboratory of Molecular Embryology, Department of Bioscience, Kitasato University School of Science, 1-15-1 Kitasato, Sagamihara, Kanagawa 228.
Hitoshi
Seiji
S
Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585.
Ikenaka
Kazuhiro
K
Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585.
Nishihara
Shoko
S
Laboratory of Cell Biology, Department of Bioinformatics, Faculty of Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577; Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Hon-cho, Kawaguchi, Saitama 332-0012, Japan. Electronic address: shoko@t.soka.ac.jp.
D000818:Animals; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology*; D004707:Endoderm / Q000378:metabolism; D005786:Gene Expression Regulation; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000166:cytology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
D006497:Heparan Sulfate; D051153:Wnt Proteins; D060508:Wnt3 Protein