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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1131-1141
RAPID COMMUNICATION
Ex Vivo Expansion of Genetically Marked Rhesus Peripheral Blood
Progenitor Cells Results in Diminished Long-Term Repopulating Ability
J.F. Tisdale,
Y. Hanazono,
S.E. Sellers,
B.A. Agricola,
M.E. Metzger,
R.E. Donahue, and
C.E. Dunbar
From the Hematology Branch, National Heart, Lung, and Blood
Institute, Bethesda, MD.
The possibility of primitive hematopoietic cell ex vivo expansion is
of interest for both gene therapy and transplantation applications. The
engraftment of autologous rhesus peripheral blood (PB) progenitors
expanded 10 to 14 days were tracked in vivo using genetic marking. Stem
cell factor (SCF)/granulocyte colony-stimulating factor
(G-CSF)-mobilized and CD34-enriched PB cells were divided
into two equal aliquots and transduced with one of two retroviral
vectors carrying the neomycin-resistance gene (neo) for 4 days
in the presence of interleukin-3 (IL-3), IL-6, and SCF in the first 5 animals, IL-3/IL-6/SCF/Flt-3 ligand (FLT) in 2 subsequent
animals, or IL-3/IL-6/SCF/FLT plus an autologous stromal monolayer
(STR) in the final 2. At the end of transduction period, one aliquot
(nonexpanded) from each animal was frozen, whereas the other was
expanded under the same conditions but without vector for a total of 14 days before freezing. After total body irradiation, both the
nonexpanded and expanded transduced cells were reinfused. Despite 5- to
13-fold higher cell and colony-forming unit (CFU) doses
from the expanded fraction of marked cells, there was greater short-
and long-term marking from the nonexpanded cells in all animals. In
animals receiving cells transduced and expanded in the presence of
IL-3/IL-6/SCF/FLT, engraftment by the marked expanded cells was further
diminished. This discrepancy was even more pronounced in the animals
who received cells transduced and expanded in the presence of FLT and
autologous stroma, with no marking detectable from the expanded cells.
Despite lack of evidence for expansion of engrafting cells, we found
that the addition of FLT and especially STR during the initial brief
transduction period increased engraftment with marked cells into a
clinically relevant range. Levels of marked progeny cells originating
from the nonexpanded aliqouts were significantly higher than that seen in previous 4 animals receiving cells transduced in the presence of
IL-3/IL-6/SCF, with levels of 10% to 20% confirmed by Southern blotting from the nonexpanded IL-3/IL-6/SCF/FLT/STR graft compared with
0.01% in the original IL-3/IL-6/SCF cohort. These results suggest
that, although expansion of PB progenitors is feasible ex vivo, their
contribution towards both short- and long-term engraftment is markedly
impaired. However, a brief transduction in the presence of specific
cytokines and stromal support allows engraftment with an encouraging
number of retrovirally modified cells.
This is a US government work. There are no restrictions on its use.
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