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Severe combined immunodeficiency mice engrafted with human T cells, B
cells, and myeloid cells after transplantation with human fetal bone marrow
or liver cells and implanted with human fetal thymus: a model for studying
human gene therapy
S Yurasov, TR Kollmann, A Kim, CA Raker, M Hachamovitch, F Wong-Staal and H Goldstein
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY
10461, USA.
To develop an in vivo model wherein human hematopoiesis occurs, we
transplanted severe combined immunodeficiency (SCID) mice with either human
fetal bone marrow (HFBM) or human fetal liver (HFL). After transplantation
of SCID mice with cultured HFBM (BM-SCID-hu mice) or HFL cells (Liv-SCID-hu
mice), significant engraftment of the mouse bone marrow (BM) and population
of the peripheral blood with human leukocytes was detected. Human
colony-forming unit-granulocyte macrophage and burst forming unit-erythroid
were detected in the BM of the BM-SCID-hu and Liv-SCID-hu mice up to 8
months after transplantation. When the HFBM or HFL cells were transduced
with a retroviral vector before transplantation, integrated retroviral
sequences were detected in human precursor cells present in the SCID mouse
BM and in leukocytes circulating in the peripheral blood (PB) up to 7
months after transplantation. The PB of the BM-SCID-hu mice also became
populated with human T cells after implantation with human thymic tissue,
which provided a human microenvironment wherein human pre-T cells from the
BM could mature. When the HFBM was retrovirally transduced before
transplantation, integrated retrovirus was detected in sorted CD4+CD8+
double positive and CD4+ single positive cells from the thymic implant and
CD4+ cells from the PB. Taken together, these data indicated that the BM of
our BM-SCID-hu and Liv-SCID-hu mice became engrafted with retrovirally
transduced human hematopoietic precursors that undergo the normal human
hematopoietic program and populate the mouse PB with human cells containing
integrated retroviral sequences. In addition to being a model for studying
in vivo human hematopoiesis, these mice should also prove to be a useful
model for investigating in vivo gene therapy using human stem/precursor
cells.
Volume 89,
Issue 5,
pp. 1800-1810,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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