title: Heparan sulfate inhibits hematopoietic stem and progenitor cell migration and engraftment in mucopolysaccharidosis I.
abstract: 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.
authors.affiliation: From the Stem Cell & Neurotherapies Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: H Angharad
authors.initials: HA
authors.lastname: Watson
authors.affiliation: From the Stem Cell & Neurotherapies Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, Stem Cell Glycobiology Group, Faculty of Physical and Engineering Sciences, University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Holley
authors.affiliation: From the Stem Cell & Neurotherapies Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Kia J
authors.initials: KJ
authors.lastname: Langford-Smith
authors.affiliation: From the Stem Cell & Neurotherapies Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Wilkinson
authors.affiliation: Matrix Biochemistry Group, Department of Biochemistry, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Bone Marrow Transplantation Unit, Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom, and.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.affiliation: Biochemical Genetics Unit, St. Mary's Hospital, Manchester M13 9WL, United Kingdom.
authors.forename: J Edmond
authors.initials: JE
authors.lastname: Wraith
authors.affiliation: Stem Cell Glycobiology Group, Faculty of Physical and Engineering Sciences, University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Catherine L R
authors.initials: CL
authors.lastname: Merry
authors.affiliation: From the Stem Cell & Neurotherapies Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, Brian.bigger@manchester.ac.uk.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Bigger
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D006085:Graft Survival; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000628:therapy*; D055153:Stem Cell Niche
chemical_list: D054377:Chemokine CXCL12; D006497:Heparan Sulfate; C515256:Cxcl12 protein, mouse
keywords: Animal Model; Bone Marrow; Bone Marrow Transplant; CXCL12; Hematopoietic Stem Cells; Heparan Sulfate; Hurler; Lysosomal Storage Disease; Migration; Mucopolysaccharidosis I