Trans-differentiation of trophoblast stem cells: implications in placental biology

Trophoblast invasion is a hallmark of hemochorial placentation. Invasive trophoblast cells replace the endothelial cells of uterine spiral arteries. The mechanism by which the invasive trophoblast cells acquire this phenotype is unknown. Here, we demonstrate that, during differentiation, a small population of trophoblast stem (TS) cells trans-differentiate into a hybrid cell type expressing markers of both trophoblast (TC) and endothelial (EC) cells. In addition, a compendium of EC-specific genes was found to be associated with TS cell differentiation. Using functional annotation, these genes were categorized into angiogenesis, cell adhesion molecules, and apoptosis-related genes. HES1 repressed transcription of EC genes in TS cells. Interestingly, differentiated TCs secrete TRAIL, but its receptor DR4 is expressed only in ECs and not in TCs. TRAIL induced apoptosis in EC but not in TC. Co-culture of ECs with TC induced apoptosis in ECs via extrinsic apoptotic pathway. These results highlight that (a) TS cells possess the potential to trans-differentiate into "trophendothelial" phenotype, regulated by HES1 and (b) trophoblast differentiation-induced TRAIL secretion directs preferential demise of ECs located in their vicinity.