SOLUBLE THROMBOPOIETIN RECEPTOR (MPL) AND GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR DIRECTLY STIMULATE PROLIFERATION OF PRIMITIVE HEMATOPOIETIC PROGENITORS OF MICE IN SYNERGY WITH STEEL FACTOR OR THE LIGAND FOR FLT3 MLK2/

In an effort to establish the specificity of the thrombopoietin (TPO) effects on murine multipotential progenitors, we tested the effects of soluble TPO receptor (sTPOR; sMpl) on multilineage colony formation t hat was supported by a combination of TPO and steel factor (SF). Surpr isingly, sTPOR did not suppress colony formation from primitive progen itors, This led to the discovery that sTPOR synergizes with SF or Flt3 /Flk2 ligand (FL) to support the formation of various types of hematop oietic colonies including multilineage colonies. The colonies supporte d by the combination of sTPOR and SF were capable of expressing both m yeloid and B-lymphoid potentials. Studies using micromanipulation and serum-free culture showed that the effects of sTPOR and SF on the prim itive progenitors are direct, not mediated by contaminating stromal ce lls, and not dependent on factors present in the serum. TPOR belongs t o the cytokine receptor group that includes granulocyte colony-stimula ting factor receptor (G-CSFR) and erythropoietin receptor (EPOR). Ther efore, we tested the effects of sG-CSFR and sEPOR on primitive progeni tors, sG-CSFR, but not sEPOR, was able to synergize with SF or FL in s upporting the proliferation of primitive progenitors. The direct effec ts of the soluble receptors appear to be mediated through interactions with their respective membrane-bound receptors expressed on the primi tive hematopoietic progenitors. (C) 1996 by The American Society of He matology.