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

Watson, HA, Holley, RJ, Langford-Smith, KJ, Wilkinson, FL, Van Kuppevelt, TH, Wynn, RF, Wraith, JE, Merry, CLR and Bigger, BW (2014) Heparan Sulfate Inhibits Hematopoietic Stem and Progenitor Cell Migration and Engraftment in Mucopolysaccharidosis I. Journal of Biological Chemistry, 289 (52). pp. 36194-36203. ISSN 0021-9258

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Official URL: https://doi.org/10.1074/jbc.M114.599944

Abstract

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. 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-/-BMHS was significantly increased and abnormally sulfated. Soluble heparinase-sensitiveGAGsfrom Idua-/-BMand 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.

Item Type:	Article
Peer-reviewed:	Yes
Date Deposited:	22 Jun 2018 09:33
Publisher:	American Society for Biochemistry and Molecular Biology
Additional Information:	This is an Open Access article published in Journal of Biological Chemistry, copyright American Society for Biochemistry and Molecular Biology.
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, ENZYME REPLACEMENT THERAPY, RISK-FACTOR ANALYSIS, ALPHA-L-IDURONIDASE, GLYCOSAMINOGLYCAN-BINDING, HURLERS-SYNDROME, MICE, TRANSPLANTATION, CHEMOKINES, DISEASE, GENE, Hematopoietic Stem Cells, Bone Marrow, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mucopolysaccharidosis I, Heparitin Sulfate, Hematopoietic Stem Cell Transplantation, Hematopoiesis, Cell Movement, Graft Survival, Chemokine CXCL12, Stem Cell Niche, Animal Model, Bone Marrow, Bone Marrow Transplant, CXCL12, Hematopoietic Stem Cells, Heparan Sulfate, Hurler, Lysosomal Storage Disease, Migration, Mucopolysaccharidosis I, Animals, Bone Marrow, Cell Movement, Chemokine CXCL12, Graft Survival, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Heparitin Sulfate, Humans, Mice, Inbred C57BL, Mice, Knockout, Mucopolysaccharidosis I, Stem Cell Niche, 06 Biological Sciences, 11 Medical And Health Sciences, 03 Chemical Sciences, Biochemistry & Molecular Biology
URI:	https://e-space.mmu.ac.uk/id/eprint/379
DOI:	https://doi.org/10.1074/jbc.M114.599944
ISSN	0021-9258

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