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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-08-2597.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 2054-2063
TRANSPLANTATION
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
A. Alex Hofling,
Carole Vogler,
Michael H. Creer, and
Mark S. Sands
From the Departments of Internal Medicine and Genetics,
Washington University School of Medicine, St Louis, MO; Department of
Pathology, Saint Louis University School of Medicine, St Louis, MO.
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
 -glucuronidase (GUSB) mutation of the mucopolysaccharidosis type VII
(MPSVII) mouse was backcrossed onto the nonobese diabetic/severe
combined immunodeficient (NOD/SCID) xenotransplantation strain.
The resulting NOD/SCID/MPSVII mice displayed the characteristic
features of lysosomal storage disease because of GUSB deficiency and
were also capable of engrafting human cells. Human CD34+
hematopoietic progenitor cells from healthy, GUSB+
donors engrafted NOD/SCID/MPSVII mice in a manner similar to that of
standard NOD/SCID mice. Six to 12 weeks following transplantation, 1%
to 86% of the host bone marrow was positive for human CD45. By 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 nonhematopoietic 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 mice receiving
transplants. 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 preclinical data regarding treatment approaches for a human disease.
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