Essential Alterations of Heparan Sulfate during the Differentiation of Embryonic Stem Cells to Sox1-EGFP Expressing Neural Progenitor Cells

¹ University of Manchester and Cancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK
² Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, USA 92093
³ MRC Centre of Stem Cell Biology, Institute for Stem Cell Research, University of Edinburgh, King's Buildings, West Mains Rd., Edinburgh, Scotland, UK; Current address: 5Division of Cell and Developmental Biology, University of Dundee, DD1 5EH
⁴ Dept. Biochemistry 280, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
⁵ Centre for Molecular Medicine, University of Manchester, UK
⁶ MRC Centre of Stem Cell Biology, Institute for Stem Cell Research, University of Edinburgh, King's Buildings, West Mains Rd., Edinburgh, Scotland, UK
⁷ MRC Centre of Stem Cell Biology, Institute for Stem Cell Research, University of Edinburgh, King's Buildings, West Mains Rd., Edinburgh, Scotland, UK; Welcome Trust Centre for Stem Cell Research, Cambridge, UK
⁸ School of Materials, Materials Science Centre, The University of Manchester, Manchester M1 7HS

^* To whom correspondence should be addressed. E-mail: catherine.merry{at}manchester.ac.uk.

	Abstract

Embryonic stem (ES) cells can be cultured in conditions that either maintain pluripotency or allow differentiation to the three embryonic germ layers. Heparan sulfate (HS), a highly polymorphic glycosaminoglycan, is a critical cell surface co-receptor in embryogenesis and in this paper we describe its structural transition from an unusually low sulfated variant in ES cells to a more highly sulfated form in FACS-purified neural progenitor cells. The characteristic domain structure of HS was retained during this transformation. However, qualitative variations in surface sulfation patterns between ES and differentiated cells were revealed using HS epitope-specific antibodies and the HS-binding growth factor FGF-2. Expression profiles of the HS modification enzymes indicated that both "early" (N-sulfotransferases) and "late" (6O and 3O-sulfotransferases) sulfotransferases contributed to the alterations in sulfation patterning. A HS-null ES line was used to demonstrate the necessity for HS in neural differentiation. HS is a co-receptor for many of the protein effectors implicated in pluripotency and differentiation (e.g., members of the FGF family, bone morphogenic proteins and fibronectin). We suggest that the stage-specific activities of these proteins are finely regulated by dynamic changes in sulfation motifs in HS chains.

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