Heparan sulfate inhibits hematopoietic stem and progenitor cell migration and engraftment in mucopolysaccharidosis I.

H Angharad Watson, Rebecca J Holley, Kia J Langford-Smith, Fiona L Wilkinson, Toin H van Kuppevelt, Robert F Wynn, J Edmond Wraith, Catherine L R Merry, Brian W Bigger

    Research output: Contribution to journalArticlepeer-review


    Mucopolysaccharidosis I Hurler (MPSI-H) is a pediatric lysosomal storage disease caused by genetic deficiencies in IDUA, coding for α-l-iduronidase. Idua(-/-) mice share similar clinical pathology with patients, including the accumulation of the undegraded glycosaminoglycans (GAGs) heparan sulfate (HS), and dermatan sulfate (DS), progressive neurodegeneration, and dysostosis multiplex. Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for Hurler patients, but reduced intensity conditioning is a risk factor in transplantation, suggesting an underlying defect in hematopoietic cell engraftment. HS is a co-receptor in the CXCL12/CXCR4 axis of hematopoietic stem and progenitor cell (HSPC) migration to the bone marrow (BM), but the effect of HS alterations on HSPC migration, or the functional role of HS in MPSI-H are unknown. We demonstrate defective WT HSPC engraftment and migration in Idua(-/-) recipient BM, particularly under reduced intensity conditioning. Both intra- but especially extracellular Idua(-/-) BM HS was significantly increased and abnormally sulfated. Soluble heparinase-sensitive GAGs from Idua(-/-) BM and specifically 2-O-sulfated HS, elevated in Idua(-/-) BM, both inhibited CXCL12-mediated WT HSPC transwell migration, while DS had no effect. Thus we have shown that excess overly sulfated extracellular HS binds, and sequesters CXCL12, limiting hematopoietic migration and providing a potential mechanism for the limited scope of HSCT in Hurler disease.
    Original languageEnglish
    Pages (from-to)36194-36203
    Number of pages9
    JournalThe Journal of biological chemistry
    Issue number52
    Publication statusPublished - 26 Dec 2014


    • Animal Model
    • Bone Marrow
    • Bone Marrow Transplant
    • CXCL12
    • Hematopoietic Stem Cells
    • Heparan Sulfate
    • Hurler
    • Lysosomal Storage Disease
    • Migration
    • Mucopolysaccharidosis I


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