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Stem cell factor, interleukin-3, and interleukin-6 promote retroviral-
mediated gene transfer into murine hematopoietic stem cells
BD Luskey, M Rosenblatt, K Zsebo and DA Williams
Howard Hughes Medical Institute, Indiana University School of Medicine,
Indianapolis 46202.
The efficiency of retroviral-mediated gene transfer into hematopoietic stem
cells (HSC) is dependent on the survival and self-renewal of HSC in vitro
during retroviral infection. We have examined the effect of prestimulation
of bone marrow with various cytokines, including the product of the Steel
gene, Steel factor or stem cell factor (SCF) (the ligand for the c-kit
receptor) on the efficiency of retroviral transduction of the human
adenosine deaminase (hADA) cDNA into murine HSC. Bone marrow cells were
prestimulated for 48 hours with hematopoietic growth factors, then
cocultivated with the packaging cell line producing the ZipPGK-ADA
simplified retrovirus for an additional 48 hours with continued growth
factor exposure. Nonadherant cells from these cocultures were injected into
lethally irradiated recipients. The content of day 12 colony-forming
unit-spleen (CFU-S12) in SCF/interleukin 6 (IL-6)-prestimulated and
cocultured bone marrow was more than threefold greater than that of
IL-3/IL-6-prestimulated bone marrow cells. All mice receiving bone marrow
cells infected with the PGK-ADA virus after prestimulation with IL-3/IL-6
or SCF/IL-6 demonstrated hADA expression in the peripheral blood after full
hematopoietic reconstitution. While all recipients of IL-3/IL-6-
prestimulated bone marrow expressed hADA at 4 months posttransplant, in
three independent experiments examining a total of 33 mice, in most
recipients of SCF/IL-6-prestimulated and infected bone marrow cells, the
expression of human enzyme was higher than IL-3/IL-6 mice. Southern blot
analysis of DNA from hematopoietic tissues from these same mice prepared at
least 4 months posttransplantation also demonstrated a higher infection
efficiency of HSC as measured by proviral integration patterns and genome
copy number analysis. These results suggest that the higher level of hADA
expression seen in mice receiving marrow prestimulated with SCF/IL-6 before
retroviral infection is due to more efficient infection of reconstituting
HSC. Other growth factor combinations were also studied; however,
prestimulation with SCF/IL-6 or IL-3/IL-6 appeared optimal. Using
retroviral-mediated gene transfer and viral integration patterns, Steel
factor (SCF) in combination with IL-6 appears to increase the survival and
self-renewal of reconstituting hematopoietic stem cells and proves useful
in effecting expression of foreign genes in transplant recipients. Such
pretreatment may also be useful in the application of retroviral transfer
methods to human cells.
Volume 80,
Issue 2,
pp. 396-402,
07/15/1992
Copyright © 1992 by The American Society of Hematology
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