Notizia

Scienziati della University of Liverpool hanno scoperto un nuovo metodo potenzialmente in grado di aiutare la riparazione dei nervi nel trattamento dei danni al midollo spinale.

Cellular/Molecular
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
Jennifer R. Higginson1,*,
Sophie M. Thompson2,*,
Alessandra Santos-Silva1,
Scott E. Guimond2,
Jeremy E. Turnbull2,†, and
Susan C. Barnett1,†
+ Author Affiliations
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary & Life Sciences, Glasgow Biomedical Research Centre, Glasgow G12 8TA, United Kingdom, and Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7XB, United Kingdom
Author contributions: S.M.T., A.S.S., S.E.G., J.E.T., and S.C.B. designed research; J.R.H. and S.M.T. performed research; J.R.H., S.M.T., and S.E.G. analyzed data; J.R.H., S.M.T., S.E.G., J.E.T., and S.C.B. wrote the paper.

    ↵*J.R.H. and S.M.T. contributed equally to this work.

    ↵†J.E.T. and S.C.B. contributed equally as senior authors.

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.