Molecular mechanisms controlling trophoblast invasion of the uterus

Abstract

In this study we have examined whether trophoblast invasiveness is aninherent property of these cells and, since in vitro placental invasion of the uterus is spatially and temporally restricted, whether loss of invasion is due to control by the decidual tissue. Using in vitro invasion assays we have shown that cultured first trimester as well as term human trophoblast cells, dissociated from the uterine microenvironment, are highly invasive. Conditioned media from first trimester human decidual cells (DCM) significantly reduced invasion of first trimester trophoblast cells. This suppression was prevented by addition of neutralizing anti-TGFβ antibody or neutralizing antibody to Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) to the DCM, and mimicked by TGFβ 1 . We have previously reported a decrease in collagenase type IV activity in the conditioned media of first trimester trophoblast cultures when TGFβ 1 was added to these cultures and that presence of neutralizing anti-TGFβ antibody in trophoblast cultures (to remove endogenous TGFβ activity) resulted in down regulation of TIMP-1 message. Here we show that removal of endogenous TGFβ in trophoblast and decidual cultures resulted in a decrease in TIMP activity in the conditioned media. These data, taken together, indicate that decidua-derived TGFβ exerts its anti-invasive action by up regulating TIMP levels in both the trophoblast and decidua. Another mechanism by which TGFβ exerts its anti-invasive role is by inducing the differentiation of invasive trophoblasts into non-proliferating, multinucleated, presumably non-invasive cells. Other mechanisms of control of trophoblast invasion remain to be determined.