In the present investigation, we provide evidence that the EPO-R on trophoblast cells and trophoblast-derived Jar cells is functional, insofar as it is phosphorylated on tyrosine residues in response to exogenous EPO (Fig. 11). Interestingly, some basal tyrosine phosphorylation was also evident, perhaps reflecting the autocrine action of endogenously produced EPO, since we have previously reported that Jar trophoblast-derived choriocarcinoma cells secrete EPO.
The finding of EPO and EPO-R expression by the placenta adds to the growing list of hematopoietic growth factors and their receptors expressed by this organ. Various populations of placental trophoblast, villous core, and uterine decidual cells have been found to express colony-stimulating factor (CSF)-1 and its receptor, c-fms product, GM-CSF and Gm-CSF receptor, granulocyte-CSF and granulocyte-CSF receptor, and stem cell factor and its receptor, c-kit product, frequently in a gestational age-specific fashion. These hematopoietic growth factors are likely to exert paracrine and/or autocrine actions in the human placenta. For example, using cultured human trophoblast cells from first-trimester placenta, CSF-1 stimulated syncytiotrophoblast formation and concomitant production of hCG and human placental lactogen. Similarly, spontaneous syncytial formation and production of these hormones by trophoblast cells in culture were prevented by addition of antibody directed against the CSF-1 receptor, c-fms product. GM-CSF also possesses these differentiating effects on cultured term placental tropho-blast cells. It will be interesting in future studies to determine whether endogenously derived EPO has a similar role in promoting placental cell growth or differentiation.