The maternal-facing surface of the human placenta is covered by a huge, multinucleate cell called the syncytiotrophoblast (ST) which grows via fusion of the underlying progenitor villous cytotrophoblasts (vCTs). vCTs undergo morphological changes in the run-up to fusion, including the formation of apical membrane projections, but little is known about the mechanisms regulating the fusion process. Here, Meghan Riddell and colleagues establish a human placental explant model, and use trypsin to remove the ST and expose the vCTs. Over time, these vCTs fuse to regenerate the large ST, thus providing a useful system for investigating the fusion process. The authors find that vCTs in trypsin-treated explants have a larger apical surface area than the controls, and scanning electron microscopy reveals that this is due to an increased occurrence of microvilli on the apical cell membrane. These microvilli are also present in trophoblast stem cell organoids and first trimester placentas. Previous work had shown that the microvilli stabiliser ezrin is present in vCT apical membrane projections, and the authors find that inhibiting ezrin affects early endosome polarisation in the vCTs and impairs fusion. Perturbing the apical localisation of CD98, a pro-fusogenic protein, also impairs vCT fusion. Overall, this work suggests that the formation of apical microvilli is crucial for promoting vCT fusion and ST formation.
