Caspase 8 and human villous cytotrophoblast differentiation

The fusion of villous cytotrophoblast into the placental syncytium is the quintessential process in maintenance of a healthy pregnancy. Efficient fusion requires a phosphatidylserine (PS)-rich cytotrophoblast surface, expression of fusion proteins, cessation of cell cycling, and rearrangement of cytoskeleton to accommodate membrane joining. Significant debate surrounds the potential role of apoptosis-related proteins, particularly caspase 8. The hypothesis that caspase 8 proteolytic activity is required for villous cytotrophoblast syncytialization rests on a foundation of three specific claims; cytotrophoblast PS efflux is an indication of early apoptosis, caspase 8 activation precedes intercellular fusion, and inhibition of caspase 8 proteolytic activity diminishes syncytialization. Our analysis of these claims reveals weaknesses that justify a reevaluation of the role of caspase 8 in villous cytotrophoblast fusion. In models of physiologic intercellular fusion, including villous cytotrophoblast, PS efflux is unrelated to apoptosis and is controlled by ATP-dependent transporters. Only a small amount of prefusion activation of caspase 8 occurs in mononuclear cytotrophoblast, and the significance remains controversial. Specific caspase 8 inhibitions with specific peptide inhibitors or antisense oligonucleotides or silencing with siRNA substantiate potential differentiation-related roles, unrelated to initiation of intercellular fusion, for both procaspase 8 and activated caspase 8. From this analysis a new and testable model of villous cytotrophoblast differentiation and fusion is presented.