Differential ability of flt3-ligand, interleukin-11, and Steel factor to support the generation of B cell progenitors and myeloid cells from primitive murine fetal liver cells.

A variety of factors produced by stromal fibroblasts, including Flt3-ligand (FL), interleukin-11 (IL-11), Steel factor (SF), and IL-7, have been implicated in stimulating the production of pre-B cells and myeloid cells from primitive hematopoietic precursors. To investigate their relative roles in this process, either as single-acting or synergistic agents, we compared the yield and types of cells produced after 2 weeks from small numbers of Sca-1+ Lin- (i.e., B220-, Ly-1-, Gr-1-, and Ter-119-) day 14.5 murine fetal liver cells placed in stromal cell-free cultures containing all possible combinations of FL, SF, IL-7, and IL-11. None of these factors alone supported the production (or survival) of any cells beyond 1 week: only pairs of factors consisting of either FL or SF plus either IL-11 or IL-7 were effective in this regard, with FL plus IL-11 being the most potent pair (approximately 7 x 10(4) cells obtained per 100 Sca-1+ Lin- input cells). The maximum numbers of cells were produced in the presence of FL, IL-11, and IL-7: these included both B220+ and Mac-1+/Gr-1+ cells (approximately 10(6) and approximately 2 x 10(5), respectively, per 100 Sca-1+ Lin- input cells). Both of these lineages were also obtained with each of the other possible three-factor combinations, albeit with variable effectiveness. Omission of either FL or IL-7 caused the greatest reduction in the yield of B220+ cells (approximately 130-fold and approximately 80-fold, respectively). Omission of IL-11 and, to a lesser extent, FL caused the greatest reduction in the yield of Mac-1+/Gr-1+ cells (approximately 90-fold and approximately 3-fold, respectively). When fetal calf serum was replaced with a defined serum substitute, the out put of B220+ cells remained the same but myelopoiesis was consistently enhanced (approximately 5- to 20-fold). These findings support a model involving factor redundancy in the extracellular signals required to stimulate the production and amplification of both lymphoid and myeloid cells from early Sca-1+ Lin- cells. They also reveal quantitative differences in the abilities of different competent factor combinations to promote this process, which may be further modulated by the presence of undefined serum components.