Apoptosis and Trophoblast Fusion

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Common pregnancy complications, such as intrauterine growth restriction (IUGR) and miscarriage, are strongly associated with abnormal development of the placenta. Defective placentation may result from exogenous environmental or maternal factors or from inborn genetic anomalies. However, our understanding of the cellular basis of IUGR or miscarriage is blocked by our ignorance about the process of normal placental development. We are cognizant that normal human placental development is dependent on differentiation of the villous cytotrophoblast culminating in intercellular fusion into the expanding syncytiotrophoblast on the placental surface. Syncytialization involves several processes, particularly cessation of cellular proliferation, redistribution of plasma membrane phospholipids to form a phosphatidylserine (PS)-rich exofacial surface, expression and insertion of fusion proteins into the plasma membrane, and rearrangement of actin cytoskeletal elements. Our preliminary data suggest that several apoptosis-related proteins, particularly caspases 3, 8, and 14, may be critical participants in trophoblast differentiation. The aim of this application is to investigate the role of these caspases in villous cytotrophoblast differentiation. We will use both primary villous cytotrophoblast cultures and a BeWo choriocarcinoma model. Using peptide inhibitors and gene silencing, we will determine the role of caspases 3, 8, and 14 in individual components of the syncytialization process (PS efflux, G1 arrest, cytoskeletal rearrangement, fusion protein expression, hCG production). Additional studies will evaluate the role of signal transduction through NFκB. The ultimate goal of this investigation is to identify the critical components controlling the mechanism of villous cytotrophoblast differentiation. Unexplained IUGR and miscarriage are common complications that lead to death of a child or to a severely compromised newborn requiring extensive care in newborn intensive care units. With the information obtained through this research, we can begin to investigate the placental defects that may explain IUGR or miscarriage, and thereby design diagnostic tests or interventions to decrease the risk of these complications.