EFFECTS OF COLONY-STIMULATING FACTOR-I ON HUMAN EXTRAVILLOUS TROPHOBLAST GROWTH AND INVASION

Colony stimulating factor (CSF)-1 has been localized in a variety of t issues and shown to influence proliferation and differentiation oi num erous cell types. Messenger RNA and protein products of CSF-1 and its receptor (c-fms) have been identified in the human placenta and decidu a. We examined whether CSF-1 and c-fms mRNA and protein are expressed by normal human first trimester invasive extravillous trophoblast (EVT ) cells propagated in culture and whether CSF-1 influences proliferati on and/or invasion of these cells. CSF-1 mRNA and protein expression w as determined by RT-PCR and immunofluorescence microscopy. Proliferati on was assessed by the cellular uptake of tritiated thymidine and inva sion was evaluated by Matrigel invasion assay as well as Northern blot analysis of mRNA expression for invasion-associated enzymes and their inhibitors. Results revealed that normal invasive EVT cells in cultur e express both CSF-1 and c-fms mRNA and protein. Under serum-free cond itions, exogenous CSF-1 greatly stimulated the proliferation of these cells. CSF-1 neutralizing and c-fms receptor blocking antibody (Ab) ea ch abolished the growth stimulatory effects oi CSF-1, indicating that CSF-1 and c-fms interaction was responsible for these effects. In fact , c-fins Ab alone reduced proliferation to below background levels. Wh ile exogenous CSF-1 bailed to influence EVT cell invasiveness, Norther n blot analysis of mRNA indicated a slight upregulation oi the invasio n-associated enzyme 72 kDa type IV collagenase as well as its natural inhibitor tissue inhibitor of metalloprotease (TIMP)-1, so that the ba lance between the two remained unaltered. These findings suggest that CSF-1 may represent an autocrine (and possibly paracrine) growth stimu latory factor for the invasive trophoblast cells in situ with no net e ffect on their invasiveness.