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Ex vivo expansion of enriched peripheral blood CD34+ progenitor cells by
stem cell factor, interleukin-1 beta (IL-1 beta), IL-6, IL-3,
interferon-gamma, and erythropoietin
W Brugger, W Mocklin, S Heimfeld, RJ Berenson, R Mertelsmann and L Kanz
Albert-Ludwigs University Medical Center, Department of Hematology and
Oncology, Freiburg, Germany.
To provide sufficient numbers of peripheral blood progenitor cells (PBPCs)
for repetitive use after high-dose chemotherapy, we investigated the
ability of hematopoietic growth factor combinations to expand the number of
clonogenic PBPCs ex vivo. Chemotherapy plus granulocyte colony-stimulating
factor (G-CSF) mobilized CD34+ cells from 18 patients with metastatic solid
tumors or refractory lymphomas were cultured for up to 28 days in a liquid
culture system. The effects of interleukin-1 beta (IL-1), IL-3, IL-6,
granulocyte-macrophage-CSF (GM-CSF), G-CSF, macrophage-CSF (M-CSF), stem
cell factor (SCF), erythropoietin (EPO), leukemia inhibitory factor (LIF),
and interferon- gamma, as well as 36 combinations of these factors were
tested. A combination of five hematopoietic growth factors, including SCF,
EPO, IL-1, IL-3, and IL-6, was identified as the optimal combination of
growth factors for both the expansion of total nucleated cells as well as
the expansion of clonogenic progenitor cells. Proliferation peaked at days
12 to 14, with a median 190-fold increase (range, 46- to 930- fold) of
total clonogenic progenitor cells. Expanded progenitor cells generated
myeloid (colony-forming unit-granulocyte-macrophage), erythroid
(burst-forming unit-erythroid), as well as multilineage (colony-forming
unit-granulocyte, erythrocyte, monocyte, megakaryocyte) colony-forming
units. The number of multilineage colonies increased 250- fold (range, 33-
to 589-fold) as compared with pre-expansion values. Moreover, the absolute
number of early hematopoietic progenitor cells (CD34+/HLA-DR-;
CD34+/CD38-), as well as the number of 4-HC-resistant progenitors within
expanded cells increased significantly. Interferon- gamma was shown to
synergize with the 5-factor combination, whereas the addition of GM-CSF
significantly decreased the number of total clonogenic progenitor cells.
Large-scale expansion of PB CD34+ cells (starting cell number, 1.5 x 10(6)
CD34+ cells) in autologous plasma supplemented with the same 5-factor
combination resulted in an equivalent expansion of progenitor cells as
compared with the microculture system. In summary, our data indicate that
chemotherapy plus G-CSF-mobilized PBPCs from cancer patients can be
effectively expanded ex vivo. Moreover, our data suggest the feasibility of
large- scale expansion of PBPCs, starting from small numbers of PB CD34+
cells. The number of cells expanded ex vivo might be sufficient for
repetitive use after high-dose chemotherapy and might be candidate cells
for therapeutic gene transfer.
Volume 81,
Issue 10,
pp. 2579-2584,
05/15/1993
Copyright © 1993 by The American Society of Hematology
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