title: Differential sulfation remodelling of heparan sulfate by extracellular 6-O-sulfatases regulates fibroblast growth factor-induced boundary formation by glial cells: implications for glial cell transplantation.
abstract: Previously, it has been shown that rat Schwann cells (SCs), but not olfactory ensheathing cells (OECs), form a boundary with astrocytes, due to a SC-specific secreted factor. Here, we identify highly sulfated heparan sulfates (HSs) and fibroblast growth factors (FGFs) 1 and 9 as possible determinants of boundary formation induced by rat SCs. Disaccharide analysis of HS in SC-conditioned and rat OEC-conditioned media showed that SCs secrete more highly sulfated HS than OECs. The dependence of the boundary-forming activity on high levels of sulfation was confirmed using a panel of semisynthetic modified heparins with variable levels of sulfation. Furthermore, extracellular HS 6-O-endosulfatase enzymes, Sulf 1 and Sulf 2, were expressed at a significantly lower level by SCs compared with OECs, and siRNA reduction of Sulfs in OECs was, in itself, sufficient to induce boundary formation. This demonstrates a key role for remodelling (reduction) of HS 6-O-sulfation by OECs, compared with SCs, to suppress boundary formation. Furthermore, specific anti-FGF1 and anti-FGF9 antibodies disrupted SC-astrocyte boundary formation, supporting a role for an HS sulfation-dependent FGF signaling mechanism via FGF receptors on astrocytes. We propose a model in which FGF1 and FGF9 signaling is differentially modulated by patterns of glial cell HS sulfation, dependent on Sulf 1 and Sulf 2 expression, to control FGF receptor 3-IIIb-mediated astrocytic responses. Moreover, these data suggest manipulation of HS sulfation after CNS injury as a potential novel approach for therapeutic intervention in CNS repair.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary & Life Sciences, Glasgow Biomedical Research Centre, Glasgow G12 8TA, United Kingdom.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Higginson
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Thompson
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santos-Silva
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.forename: Susan C
authors.initials: SC
authors.lastname: Barnett
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D008297:Male; D009457:Neuroglia / Q000378:metabolism* / Q000637:transplantation; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D017468:Receptors, Fibroblast Growth Factor; D013429:Sulfatases; D015238:Sulfotransferases; C507077:Sulf1 protein, rat; C547680:Sulf2 protein, rat