Distinct actions of Flt3 ligand and stem cell factor on myeloid lineage selection and maturation of granulocytes versus macrophages.
Flt3/Flk2 ligand (FL) and stem cell factor (SCF; c-kit ligand) interact with different but related surface receptor tyrosine kinases expressed on early hematopoietic cells. Both FL and SCF stimulate the proliferation of stem cells and progenitors, but the mechanisms by which these cytokines exert their functions are currently unknown. Here we show that FL and SCF have different effects on myeloid differentiation and lineage selection of early hematopoietic cells using a defined subpopulation of mouse bone marrow (BM) expressing c-Kit but lacking mature lineage markers (c-Kit+Lin-). SCF, together with IL-6, induced the differentiation of a large fraction of these progenitor cells toward mature granulocytes and to a lesser extent toward monocytes. In contrast, FL combined with IL-6 favored differentiation into mature monocytes and macrophages, and very few if any granulocytes could be identified. When FL and SCF were analyzed for their ability to support growth of multilineage erythroid colonies (pre-CFCmulti) and myeloid-committed colony-forming progenitors of granulocytes and monocytes (CFC-G/M), a clear discrepancy was also found. Both FL and SCF had synergistic effects on the proliferation of immature cells with blast-like morphology, but the expansion of pre-CFCmulti and CFC-G/M was favored by SCF but not by FL. FL synergized with both SCF and IL-6 with respect to proliferative response and maintenance of undifferentiated cells; however, the numbers of CFC-G/M after 7 or 14 days in culture were significantly lower than those observed with SCF combined with IL-6. Interestingly, in contrast to SCF, no pre-CFCmulti was recovered from BM cells expanded in the presence of FL and IL-6.
Dannaeus
K
K
Department of Pathology, University Hospital, University of Uppsala, Sweden.
Nilsson
K
K
Jönsson
J I
JI
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D004357:Drug Synergism; D015672:Erythroid Precursor Cells / Q000166:cytology; D006098:Granulocytes / Q000166:cytology*; D006410:Hematopoiesis; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology*; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019089:Stem Cell Factor / Q000494:pharmacology*
D015850:Interleukin-6; D008565:Membrane Proteins; D019089:Stem Cell Factor; C084881:flt3 ligand protein