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Retroviral transduction of human progenitor cells: use of granulocyte
colony-stimulating factor plus stem cell factor to mobilize progenitor
cells in vivo and stimulation by Flt3/Flk-2 ligand in vitro
NJ Elwood, H Zogos, T Willson and CG Begley
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital,
Parkville, Victoria, Australia.
The clinical application of gene transfer is hindered by the availability
of the multipotential stem cells and the difficulty in obtaining efficient
retroviral transduction. To assess potential means by which gene transfer
into human hemopoietic stem cells might be enhanced, the retroviral
transduction efficiency of human bone marrow cells (BM) or peripheral blood
progenitor cells (PBPC) was compared at multiple time points after in vivo
administration of granulocyte colony- stimulating factor (G-CSF). This was
further compared with the transduction efficiency of cells mobilized with
G-CSF plus stem cell factor (SCF) in a cohort of patients randomized to
receive either one or two growth factors and with normal BM function. Using
the LNL6 retrovirus, retroviral transduction efficiencies of up to 19% were
observed for both PBPC and BM (n = 26 patients). There was at least a
100-fold increase in PBPC with G-CSF alone and a further 30-fold increase
in the total number of progenitor cells available for retroviral
transduction using the combination of SCF plus G-CSF. However, pretreatment
of patients with G-CSF with or without SCF did not enhance the retroviral
infectability of growth factor-mobilized progenitor cells. The effect of
the growth factor, Flk-2/Flt3 ligand (FL), was also examined with respect
to retroviral transduction efficiency of human progenitor cells. FL plus
IL-3 in vitro increased the retroviral transduction efficiency up to
eightfold compared with results observed using other combinations of
cytokines tested (P < .001). These findings have clinical implications
both for increasing the number of target cells for in vivo
gene-marking/gene-therapy studies and improving the efficiency of gene
transfer.
Volume 88,
Issue 12,
pp. 4452-4462,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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