Mechanisms Controlling Placental Invasion Of The Uterus

Trophoblast cells of the placenta have evolved mechanisms to invade the uterus inclusive of its blood vessels. This invasion is strictly controlled and, in humans, usually continues until mid-gestation. This study was primarily designed to determine (a) whether trophoblast cells are pre-programmed to stop invading and if not, (b) the source and nature of the mechanisms which control their invasiveness in situ. To address these questions, pure cultures of human first trimester and term trophoblast cells were established and characterized. Both cell populations were found to be highly invasive in vitro, indicating that their invasiveness in situ must be controlled by the microenvironment. Examination of the in vitro invasive ability of first trimester cells in the presence or absence of conditioned media from cultures of uterine decidual cells, pure known decidual products, or antibodies against these products revealed that the decidual tissue secretes two soluble factors which inhibit trophoblast invasion: TGF{dollar}\beta{dollar} and tissue inhibitor of metalloproteinases (TIMP)-1. Immunocytochemical studies localized TGF{dollar}\beta{dollar} in situ in first trimester and term decidual and trophoblastic tissues. To determine the mechanisms of the control of invasiveness, first trimester cells were cultured in the presence or absence of pure TGF{dollar}\beta\sb1{dollar} or a neutralizing antibody against both TGF{dollar}\beta\sb1{dollar} and TGF{dollar}\beta\sb2{dollar}. Presence of exogenous and/or endogenous TGF{dollar}\beta{dollar} resulted in (a) down-regulation of collagenase type IV activity; (b) major increase in TIMP activity and TIMP-1 mRNA; (c) no change in TIMP-2 mRNA level; (d) a minor increase in 72-kDa type IV collagenase mRNA level; (e) decrease in cell proliferation and increase in the proportion and number of non-invasive multinucleated cells. In contrast, JAR choriocarcinoma cells responded to TGF{dollar}\beta{dollar} by increased proliferation and in vitro invasiveness, whereas JEG-3 choriocarcinoma cells showed no increase in invasiveness and a decrease in proliferation. These results indicate that (a) first trimester and term trophoblast cells are inherently invasive; (b) their invasiveness is environmentally controlled by TGF{dollar}\beta{dollar} and TIMP-1; (c) TGF{dollar}\beta{dollar} mediates this control by inducing TIMP-1 and by promoting trophoblast differentiation into non-invasive multinucleated cells; (d) this TGF{dollar}\beta{dollar}-mediated control is deranged in certain choriocarcinomas