Heparan Sulfate Inhibits Hematopoietic Stem and Progenitor Cell Migration and Engraftment in Mucopolysaccharidosis I

• Published in: The Journal of biological chemistry 2014-12, Vol.289 (52), p.36194-36203
• Main Authors: Watson, H. Angharad, Holley, Rebecca J., Langford-Smith, Kia J., Wilkinson, Fiona L., van Kuppevelt, Toin H., Wynn, Robert F., Wraith, J. Edmond, Merry, Catherine L.R., Bigger, Brian W.
• Format: Article
• Language: English
• Subjects: Animal Model; Animals; Bone Marrow; Bone Marrow - pathology; Bone Marrow Transplant; Cell Movement; Chemokine CXCL12 - metabolism; CXCL12; Glycobiology and Extracellular Matrices; Graft Survival; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hematopoietic Stem Cells - physiology; Heparan Sulfate; Heparitin Sulfate - pharmacology; Humans; Hurler; Lysosomal Storage Disease; Mice, Inbred C57BL; Mice, Knockout; Migration; Mucopolysaccharidosis I; Mucopolysaccharidosis I - therapy; Stem Cell Niche
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.599944

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. Hematopoietic stem cell transplant in mucopolysaccharidosis I (MPSI) patients often results in graft failure. In mice with MPSI we link reduced hematopoietic engraftment post-transplant to accumulated overly-sulfated extracellular heparan sulfate. Excess extracellular heparan sulfate alters cytokine gradient formation, restricting stem cell migration. This provides a mechanistic insight into the observed engraftment difficulties seen in patients.