The flt3 ligand promotes the survival of primitive hemopoietic progenitor cells with myeloid as well as B lymphoid potential. Suppression of apoptosis and counteraction by TNF-alpha and TGF-beta.
The recently cloned fIt3 ligand (FL) potently enhances hemopoietic growth factor-induced growth of primitive hemopoietic progenitors. In agreement with previous reports, we found FL alone to be a weak mitogen for primitive Lin-Sca-1+ murine bone marrow progenitors. Using delayed addition of growth-promoting cytokines, we demonstrate that FL potently promotes the in vitro survival of Lin-Sca-1+ progenitors responsive to a potent myeloid growth factor combination (FL, stem cell factor (SCF), granulocyte CSF (G-CSF), and IL-1 alpha). Whereas no such progenitors survived in cultures supplemented with medium alone, 33% survived in FL compared with 75 and 13% in the presence of SCF and IL-1 alpha, respectively. These results were obtained when cells were plated individually, suggesting that the viability-promoting effect of FL is mediated directly on the progenitors. Whereas SCF was superior to FL in promoting the survival of FL-, SCF-, G-CSF-, and IL-1 alpha-stimulated Lin-Sca-1+ progenitors, FL was more efficient than SCF at promoting the survival of progenitors with a B cell potential, as measured by their ability to produce B220+ cells in response to delayed addition of FL, SCF, and IL-7. Seventy-one percent of the B220+ cell production could be recovered following 40-h incubation with FL compared with 2% in response to SCF. Analysis of day 12 spleen CFU content after 40-h preincubation of Lin-Sca-1+ cells in FL or SCF demonstrated that SCF maintained 64% of the day 12 spleen CFU, whereas only 16% survived in the presence of FL. Finally, there was no significant difference between the ability of FL and SCF to maintain the viability of long-term culture-initiating cells (25 and 32%, respectively). The ability of FL to promote the survival of Lin-Sca-1+ progenitor cells was reflected by the finding that FL also suppressed apoptosis. Finally, TGF-beta abrogated and TNF-alpha potently counteracted the survival-promoting effect of FL. Thus, FL promotes the survival of primitive hemopoietic progenitor cells, in particular those with an inherent B lymphoid potential.
Veiby
O P
OP
Hipple Cancer Research Center, Dayton, OH 45439, USA.
Jacobsen
F W
FW
Cui
L
L
Lyman
S D
SD
Jacobsen
S E
SE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology*; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011828:Radiation Chimera; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3
D016298:Hematopoietic Cell Growth Factors; D007375:Interleukin-1; D015851:Interleukin-7; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3