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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-08-2597.
Submitted August 23, 2002
Accepted October 11, 2002
Engraftment of human CD34+ cells leads to widespread distribution of donor-derived cells and correction of tissue pathology in a novel murine xenotransplantation model of lysosomal storage disease
August Alex Hofling, Carole Vogler, Michael H Creer, and Mark S Sands*
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO, USA
* Corresponding author; email: msands{at}imgate.wustl.edu.
A novel murine system was developed to study the in vivo localization of xenotransplanted human cells and assess their therapeutic effect in an authentic model of disease. The ß-glucuronidase (GUSB) mutation of the mucopolysaccharidosis type VII (MPSVII) mouse was backcrossed onto the NOD/SCID xenotransplantation strain. The resulting NOD/SCID/MPSVII mice displayed the characteristic features of lysosomal storage disease due to GUSB deficiency and were also capable of engrafting human cells. Human CD34+ hematopoietic progenitor cells from normal, GUSB-positive donors engrafted NOD/SCID/MPSVII mice in a manner similar to that of standard NOD/SCID mice. Six to 12 weeks following transplantation, 1%-86% of the host bone marrow was positive for human CD45. Using a GUSB-specific histochemical assay, human engraftment was detected with single-cell sensitivity not only in well characterized hematopoietic tissues like bone marrow, spleen, lymph node and thymus, but also in other non-hematopoietic organs like liver, kidney, lung, heart, brain, and eye. Quantitative measurements of GUSB activity confirmed this expansive tissue distribution. The GUSB-specific assays were validated for their accuracy in identifying human cells through colocalization of human CD45 expression with GUSB activity in tissues of transplanted mice. An analysis of the therapeutic effects of engrafted human cells revealed a reduction of pathologic storage material in host organs including the bone, spleen, and liver. Such xenotransplantation experiments in the NOD/SCID/MPSVII mouse represent a powerful approach to both study the in vivo biology of human cells and gather pre-clinical data regarding treatment approaches for a human disease.
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