title: A genetically myeloablated MPS VII model detects the expansion and curative properties of as few as 100 enriched murine stem cells.
abstract: Causes of transplantation failures are often difficult to assess due to our inability to monitor hematopoietic stem cell (HSC) homing, distribution, and amplification in situ. We have developed a mouse model that permits histochemical localization of 1000-fold enriched HSC and quantification of their long-term expanded progeny in situ. The mice are genetically myeloablated (c-kit receptor mutated, W41/W41) and are beta-glucuronidase null (GUSB ; gus(mps)/gus(mps)). The GUSB- mice with mucopolysaccharidosis type VII (MPS VII), like a large number of human patients with similar diseases, have systemic lysosomal storage disease that leads to premature death. Congenic GUSB+, Lineage(lo), Sca-1(hi), c-Kit(hi), Hoechst(lo) HSC, at doses of 30, 100, 250, and 425 cells, implanted and amplified in adult W41/W41, gus(mps)/gus(mps) recipients in a dose-dependent manner. At autopsy, primary recipients of 100 and 425 donor cells had histologically identifiable donor GUSB+ cells in multiple sites and showed both myeloid and lymphoid expansion in bone marrow. Donor cells were rare in the liver and spleen of 100-cell recipients, but lysosomal storage was significantly reduced. The life span was significantly extended in engrafted recipients of 250 (36.7 +/- 3.84 weeks,p = 0.0316) and 425 (40.7 +/-1.53 weeks,p = 0.0033) cells compared to untreated mice (26.4 +/- 1.53 weeks). Secondary hosts of marrow from the recipients of 425 cells demonstrated continued expansion of the GUSB+ cells. Results indicate the genetically myeloablated MPS VII mice can be used to trace and enumerate donor cells long-term and to follow early engraftment events in situ.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. bws@jax.org
authors.forename: B W
authors.initials: BW
authors.lastname: Soper
authors.forename: T M
authors.initials: TM
authors.lastname: Duffy
authors.forename: C A
authors.initials: CA
authors.lastname: Vogler
authors.forename: J E
authors.initials: JE
authors.lastname: Barker
mesh_terms: D000818:Animals; D002452:Cell Count; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D008817:Mice, Mutant Strains; D016538:Mucopolysaccharidosis VII / Q000628:therapy*