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.
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Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. neal.rote@case.edu
Wei
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Xu
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D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002454:Cell Differentiation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D010920:Placenta / Q000201:enzymology* / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism
D061945:Caspase Inhibitors; D011257:Pregnancy Proteins; D053181:Caspase 8