| Research Abstract |
Eryhropoietin(EPO) is the primary humoral regulator of erythropoiesis and no other factor has previously been reported to support proliferation and terminal maturation of erythroid cells from hemopoietic stem cells. We found that stimulation of gp130 by a combination of recombinant human soluble IL-6 receptor (sIL-6R) and IL-6 can support proliferation, differentiation and terminal maturation of erythroid cells in the absence of EPO from purified human CD34^+ cells in suspensin culture containing stem cell factor (SCF) or flk2/flt3 ligand. The addition of anti-gp130 mAbs but not anti-EPO Ab to the same culture completely abrogated the generation of erythroid cells. These results clearly demonstrate that mature erythroid cells can be emerged from hemopoietic progenitors without EPO in vitro. HML/SE is a GM-CSF-or SCF-dependent cell line established from a children with M7 leukemia. Although HML/SE cells neither proliferate nor in the presense of EPO alone, these cells can proliferate an
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d produce hemoglobin by a combinaation of recombinant human sIL-6R and IL-6. SCF and activation of gp130 activated the human EPO receptor promoter and induced EPO receptor gene expression. Taken together, we speculate that HML/SE cells acquired responsiveness to EPO via the EPO receptor induced by SCF and gp130 signallings. Mutation analysis of putative transcription factor binding sites in the human EPO receptor promoter suggested that Spl, rather than the GATA-1 binding site, contributed to the induction of the hEPOR gene. While it is well documented that hematopoietic stem cells and primitive progenitors require both an early-actimg cytokine and a kineage specific cytokine to differntiate to a certain lineage, related mechanisms are not well understood. Together with the previous reports that human sera contain derectable levels of sIL-6R,IL-6 and SCF,normal erythropoiesis may be regulated physiologically by two different pathways ; the EPO-mediated signalling and a novel mechanism with gp130 in combination with c-KIT signalling. Less
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