Synergistic effect of FLT-3 ligand on the granulocyte colony-stimulating factor-induced mobilization of hematopoietic stem cells and progenitor cells into blood in mice.
We have previously shown that FLT-3 ligand (FL) mobilizes murine hematopoietic primitive and committed progenitor cells into blood dose-dependently. Whether FL also acts synergistically with granulocyte colony-stimulating factor (G-CSF) to induce such mobilization has now been investigated. Five- to 6-week-old C57BL/6J mice were injected subcutaneously with recombinant human G-CSF (250 microg/kg), Chinese hamster ovarian cell-derived FL (20 microg/kg), or both cytokines daily for 5 days. The number of colony-forming cells (CFCs) in peripheral blood increased approximately 2-, 21-, or 480-fold after administration of FL, G-CSF, or the two cytokines together, respectively, for 5 days. The number of CFCs in bone marrow decreased after 3 days but was increased approximately twofold after 5 days of treatment with G-CSF. The number of CFCs in the bone marrow of mice treated with both FL and G-CSF showed a 3.4-fold increase after 3 days and subsequently decreased to below control values. The number of CFCs in spleen was increased 24.2- and 93.7-fold after 5 days of treatment with G-CSF alone or in combination with FL, respectively. The number of colony-forming unit-spleen (CFU-S) (day 12) in peripheral blood was increased 13.2-fold by G-CSF alone and 182-fold by G-CSF and FL used together after 5 days of treatment. Finally, the number of preCFU-S mobilized into peripheral blood was also increased by the administration of FL and G-CSF. These observations show that FL synergistically enhances the G-CSF-induced mobilization of hematopoietic stem cells and progenitor cells into blood in mice, and that this combination of growth factors may prove useful for obtaining such cells in humans for transplantation.
Sudo
Y
Y
Second Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyoku, Japan.
Shimazaki
C
C
Ashihara
E
E
Kikuta
T
T
Hirai
H
H
Sumikuma
T
T
Yamagata
N
N
Goto
H
H
Inaba
T
T
Fujita
N
N
Nakagawa
M
M
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D016466:CHO Cells; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D004357:Drug Synergism; D004921:Erythropoietin / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D007377:Interleukin-3; D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor