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Long-term maintenance of hematopoiesis in irradiated mice by retrovirally
transduced peripheral blood stem cells
N Drize, J Chertkov, E Sadovnikova, S Tiessen and A Zander
Hematological Scientific Center, Russian Academy of Medical Science,
Moscow, Russia.
Mobilized peripheral blood stem cells (PBSC) are used as a source of
hematopoietic stem cells for transplantation and gene therapy. It is still
unclear, however, whether the PBSC are fully equivalent to normal bone
marrow hematopoietic stem cells and whether they are able to provide
long-term function of transgene in reconstituted mice. In the present
study, mobilized PBSC from male mice were transduced with human adenosine
desaminase gene (hADA) and were used for reconstitution of lethally
irradiated female mice. At 1 1/2, 3, 6, 9, and 12 months after
reconstitution, the bone marrow cells were repeatedly collected from each
mouse under light anesthesia and the number of colony-forming unit- spleen
(CFU-S), spleen repopulating ability (SRA), and the integration of human
ADA gene were studied in CFU-S-derived colonies by polymerase chain
reaction (PCR) and Southern blot hybridization analyses. After 9 months,
the proportion of donor CFU-S detected by PCR with a Y- chromosome-specific
probe in mice reconstituted with mobilized PBSC was 75.3% +/- 6.0%, which
is similar to the concentration of donor CFU-S seen after bone marrow
transplantation. Similarly, there was no difference in the concentration of
CFU-S in mice reconstituted with transduced mobilized PBSC or bone marrow
cells. However, in both cases the CFU-S content in the bone marrow was
reduced fivefold to 10-fold compared with the concentration of CFU-S in
mice transplanted with nontransduced bone marrow. The SRA of CFU-S in mice
reconstituted with peripheral blood and bone marrow cells was the same 1.5
months posttransplantation, but after an additional 4 months, SRA of mice
reconstituted with bone marrow cells was fivefold higher as compared with
those engrafted by PBSC. The integration of the human ADA gene was observed
during 9 months in about 60% of studied CFU-S. The proportion of marked
colonies sharply decreased 1 year following reconstitution. One to 9
individually labeled clones could be shown simultaneously by Southern blot
hybridization in the same reconstituted mice during the whole period of
observation. The time of clone existence was about 3 months. We conclude
that long-term marrow repopulating cells mobilized into circulation by
treatment with granulocyte colony-stimulating factor (G-CSF) and stem cell
factor (SCF) are capable of maintaining lifelong polyclonal hematopoiesis
in reconstituted mice.
Volume 89,
Issue 5,
pp. 1811-1817,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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