title: Effect of systemic heparan sulfate haploinsufficiency on steady state hematopoiesis and engraftment of hematopoietic stem cells.
abstract: Heparan sulfate (HS) proteoglycans on stromal and hematopoietic stem/progenitor cells (HSPC) help form the stem cell niche, co-localize molecules that direct stem cell fate, and modulate HSPC homing and retention. Inhibition of HS function mobilizes marrow HSPC. In vitro, HSPC maintenance is influenced by stromal HS structure and concentration. Because inhibition of HS activity or synthesis may be developed for HSPC transplantation, it is important to examine if systemic HS deficiency influences hematopoiesis in vivo. In a transgenic mouse model of HS haploinsufficiency, we examined endogenous hematopoiesis and engraftment of allogeneic bone marrow. Endogenous hematopoiesis was normal except gender-specific alterations in peripheral blood monocyte and platelet counts. Donor engraftment was achieved in all mice following myeloablative irradiation, but HS deficiency in the stromal microenvironment, on HSPC, or both (the 3 test conditions), was associated with a trend towards lower donor engraftment percentage in the bone marrow. Following non-myeloablative irradiation, competitive engraftment was achieved in 22% of mice in the test conditions, vs 50% of control animals (P = 0.03). HS deficiency did not re-direct donor engraftment from bone marrow to spleen or liver. Normal HS levels in the stromal microenvironment and HSPC are required for HSPC engraftment following non-myeloablative conditioning.
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, United States; Hematology/Oncology/Transplantation Division, Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Shekels
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Buelt-Gebhardt
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, United States; Hematology/Oncology/Transplantation Division, Department of Medicine, University of Minnesota, Minneapolis, MN, United States. Electronic address: pankaj.gupta@va.gov.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D005260:Female; D015870:Gene Expression; D006085:Graft Survival / Q000235:genetics*; D057895:Haploinsufficiency / Q000276:immunology*; D006410:Hematopoiesis / Q000235:genetics* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006497:Heparan Sulfate / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics*; D012737:Sex Factors; D055153:Stem Cell Niche; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation; D000099058:Exostosin 1
chemical_list: D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1
keywords: Exostosin-1; Hematopoietic stem cell transplantation; Hematopoietic stem cells; Heparan sulfate proteoglycans; Heparitin sulfate; Mice