title: Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning.
abstract: The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes in hematopoietic stem and progenitor cell (HSPC) localization. HSPC egressed from BM to spleen after Ext1 deletion. This was associated with altered signaling in the stromal cells and with reduced vascular cell adhesion molecule 1 production by them. Further, pharmacologic inhibition of heparan sulfate mobilized qualitatively more potent and quantitatively more HSPC from the BM than granulocyte colony-stimulating factor alone, including in a setting of granulocyte colony-stimulating factor resistance. The reduced presence of endogenous HSPC after Ext1 deletion was associated with engraftment of transfused HSPC without any toxic conditioning of the host. Therefore, inhibiting heparan sulfate production may provide a means for avoiding the toxicities of radiation or chemotherapy in HSPC transplantation for nonmalignant conditions.
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferraro
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Rushdia Z
authors.initials: RZ
authors.lastname: Yusuf
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Cook
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Vionnie W C
authors.initials: VW
authors.lastname: Yu
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Ana
authors.initials: A
authors.lastname: Pardo-Saganta
authors.affiliation: Immune Cell Development and Host Defense, Research Institute of Fox Chase Cancer Center, Philadelphia, PA;
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Rahul
authors.initials: R
authors.lastname: Palchaudhuri
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Amir
authors.initials: A
authors.lastname: Schajnovitz
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA;
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: Stefania
authors.initials: S
authors.lastname: Lymperi
authors.affiliation: Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
authors.forename: Simon
authors.initials: S
authors.lastname: Mendez-Ferrer
authors.affiliation: Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
authors.forename: Raquel Del
authors.initials: RD
authors.lastname: Toro
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA;
authors.forename: Robyn
authors.initials: R
authors.lastname: Day
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA;
authors.forename: Radovan
authors.initials: R
authors.lastname: Vasic
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA;
authors.forename: Sanket S
authors.initials: SS
authors.lastname: Acharya
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA;
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA; Advanced Microscopy Program, Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Boston, MA;
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA;
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Harvard Stem Cell Institute, Cambridge, MA; Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA; and Howard Hughes Medical Institute, Cambridge, MA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA;
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001667:Binding, Competitive / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism*; D019172:Transplantation Conditioning; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D000099058:Exostosin 1
chemical_list: D000925:Anticoagulants; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins; D006493:Heparin; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D019010:Vascular Cell Adhesion Molecule-1; D000099058:Exostosin 1