3-o-sulfated heparan sulfate recognized by the antibody hs4c3 contribute to the differentiation of mouse embryonic stem cells via fas signaling3-o-sulfated硫酸乙酰肝素被抗体hs4c3导致小鼠胚胎干细胞的分化通过fas信号.pdf

3-O-Sulfated Heparan Sulfate Recognized by the Antibody HS4C3 Contribute to the Differentiation of Mouse Embryonic Stem Cells via Fas Signaling 1 1 1 1 2 Kazumi Hirano , Norihiko Sasaki , Tomomi Ichimiya , Taichi Miura , Toin H. Van Kuppevelt , Shoko Nishihara1* 1 Laboratory of Cell Biology, Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo, Japan, 2 Nijmegen Centre for Molecular Life Sciences, Department of Biochemistry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Abstract Maintenance of self-renewal and pluripotency in mouse embryonic stem cells (mESCs) is regulated by the balance between several extrinsic signaling pathways. Recently, we demonstrated that heparan sulfate (HS) chains play important roles in the maintenance and differentiation of mESCs by regulating extrinsic signaling. Sulfated HS structures are modified by various sulfotransferases during development. However, the significance of specific HS structures during development remains unclear. Here, we show that 3-O-sulfated HS structures synthesized by HS 3-O-sulfotransferases (3OSTs) and recognized by the antibody HS4C3 increase during differentiation of mESCs. Furthermore, expression of Fas on the cell surface of the differentiated cells also increased. Overexpression of the HS4C3-binding epitope in mESCs induced apoptosis and spontaneous differentiation even in the presence of LIF and serum. These data showed that the HS4C3-binding epitope was required for differentiation of mESCs. Up-regulation of the HS4C3-binding epitope resulted in the recruitment of Fas from the cytoplasm to lipid rafts on the cell surface followed by activation of Fas signaling. Indeed, th