The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors.
The recently cloned murine flt3 ligand (FL) was studied for its ability to stimulate the growth of primitive (Lin-Sca-1+) and more committed (Lin-Sca-1-) murine bone marrow progenitor cells, alone and in combination with other hematopoietic growth factors (HGFs). Whereas FL was a weak proliferative stimulator alone, it potently synergized with a number of other HGFs, including all four colony-stimulating factor (CSF), interleukin (IL) 6, IL-11, IL-12, and stem cell factor (SCF), to promote the colony formation of Lin-Sca-1+, but not Lin-Sca-1- or erythroid progenitor cells. The synergistic activity of FL was concentration dependent, with maximum stimulation occurring at 250 ng/ml, and was observed when cells were plated at a concentration of one cell per culture, suggesting that its effects are directly mediated. 2 wk of treatment with FL in combination with IL-3 or SCF resulted in the production of a high proportion of mature myeloid cells (granulocytes and macrophages), whereas the combination of FL with G-CSF, IL-11, or IL-12 resulted predominantly in the formation of cells with an immature blast cell appearance. Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40-fold after 2 wk incubation. Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells.
Jacobsen
S E
SE
Department of Immunology, Norwegian Radium Hospital, Oslo.
Okkenhaug
C
C
Myklebust
J
J
Veiby
O P
OP
Lyman
S D
SD
D000818:Animals; D004357:Drug Synergism; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D017370:Interleukin-11 / Q000494:pharmacology*; D018664:Interleukin-12 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D011828:Radiation Chimera; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D019089:Stem Cell Factor; D051941:fms-Like Tyrosine Kinase 3
D016298:Hematopoietic Cell Growth Factors; D017370:Interleukin-11; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D018664:Interleukin-12; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3