A genetically myeloablated MPS VII model detects the expansion and curative properties of as few as 100 enriched murine stem cells

Causes of transplantation failures are often difficult to assess due to our inability to monitor hematopoietic stem cell (HSC) homing, distribution, a nd amplification bl situ. We have developed a mouse model that permits hist ochemical localization of 1000-fold enriched HSC and quantification of thei r long-term expanded progeny in situ. The mice are genetically myeloablated (c-kit receptor mutated, W-41/W-41) and are beta-glucuronidase null (GUSB( -); gus(mps)/gus(mps)). The GUSB(-) mice with mucopolysaccharidosis type VI I (MPS VII), like a large number of human patients with similar diseases, h ave systemic lysosomal storage disease that leads to premature death. Conge nic GUSB(+), Lineage(lo), Sca-1(hi), c-Kit(hi), Hoechst(lo) HSC, at doses o f 30, 100, 250, and 425 cells, implanted and amplified in adult W-41/W-41, gus(mps)/gus(mps) recipients in a dose-dependent manner. At autopsy, primar y recipients of 100 and 425 donor cells had histologically identifiable don or GUSB+ cells in multiple sites and showed both myeloid and lymphoid expan sion in bone marrow. Donor cells were rare in the liver and spleen of 100-c ell recipients, but lysosomal storage was significantly reduced. The life s pan was significantly extended in engrafted recipients of 250 (36.7 +/- 3.8 4 weeks, p = 0.0316) and 425 (40.7 +/- 1.53 weeks, p = 0.0033) cells compar ed to untreated mice (26.4 +/- 1.53 weeks). Secondary hosts of marrow from the recipients of 425 cells demonstrated continued expansion of the GUSB+ c ells. Results indicate the genetically myeloablated MPS VII mice can be use d to trace and enumerate donor cells long-term and to follow early engraftm ent events in situ. (C) 1999 International Society for Experimental Hematol ogy. Published by Elsevier Science Inc.