The paradox of caspase 8 in human villous trophoblast fusion

Differentiation and subsequent fusion of villous cytotrophoblasts with the overlying syncytiotrophoblast is an essential process for growth and maintenance of the villous trophoblast layer in the human placenta. The understanding of intrinsic mechanisms behind this process is in its infancy, while the list of suggested factors, involved in intercellular fusion of trophoblasts, rapidly increased in the recent past and promises progress on this issue. The early stages of the apoptosis cascade, in particular caspase 8, was suggested to trigger differentiation of cytotrophoblasts, priming them for upcoming fusion. This may sound paradoxical, especially for those who still associate caspase activity with apoptosis only. Here, we summarize data on caspase 8 in the villous trophoblast layer, with a specific focus on localization of pro- and active forms, the sites of its activation and deactivation, and its role and regulation during fusion. Moreover, we revisit the knowledge on fusogens in the villous trophoblast, compare in vitro models for trophoblast fusion and discuss methods to quantify fusion.