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Mobilization of hematopoietic stem and progenitor cell subpopulations from
the marrow to the blood of mice following cyclophosphamide and/or
granulocyte colony-stimulating factor
S Neben, K Marcus and P Mauch
Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA
02115.
Committed progenitor cells and primitive stem cells mediate early and
sustained engraftment, respectively, after lethal irradiation and stem cell
transplantation. Peripheral blood stem cells (PBSC) from unstimulated mice
are deficient in both cell types. To study techniques to mobilize both
progenitor cells and primitive stem cells from the marrow to the blood, we
collected peripheral blood from C57BL/6 mice 6 to 7 days after a single
dose of cyclophosphamide (CY; 200 mg/kg intraperitoneally), after
recombinant human granulocyte colony- stimulating factor (rhG-CSF) (250
micrograms/kg/d twice per day subcutaneously for 4 days), or after CY
followed by G-CSF. Significant increases in white blood cell counts (1.6-
to 2.7-fold) and circulating day 8 colony-forming unit spleen (CFU-S) (11-
to 36-fold) were seen with all three mobilization methods compared with
unstimulated control mice. Transplantation of mobilized blood stem cells
into lethally irradiated hosts decreased the time to erythroid engraftment.
Blood stem cells were analyzed for primitive stem cell content by Rs, an
assay for CFU-S self-renewal, and competitive repopulation index (CRI), an
assay of long-term repopulating ability. The primitive stem cell content of
unstimulated blood was clearly deficient, but was significantly increased
following mobilization, approaching normal bone marrow levels. These
results were confirmed by an in vitro limiting dilution long-term culture
assay that measures the frequency of progenitor cells and primitive stem
cells. Mobilization following CY + G-CSF was accompanied by a marked loss
of both progenitor cells and primitive stem cells in the marrow. In
contrast, following G-CSF alone the progenitor cell and primitive stem cell
content of the marrow was unchanged. Stem cell mobilization following CY +
G-CSF was not affected by previous exposure of donors to cytosine
arabinoside or cyclophosphamide, but was significantly reduced by previous
exposure to busulfan. These data show that stem cell content in the blood
may reach near-normal marrow levels after mobilization, the mobilization
from the marrow to the blood is temporary and reversible, the specific
technique used may mobilize different subpopulations of stem cells, and the
type of prior chemotherapy may influence the ability to mobilize stem cells
into the blood.
Volume 81,
Issue 7,
pp. 1960-1967,
04/01/1993
Copyright © 1993 by The American Society of Hematology
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