As the human placenta forms, progenitor villous cytotrophoblasts (vCTs) undergo cell fusion to produce a multinucleate cell called the syncytiotrophoblast (ST). When this process goes wrong, it can lead to conditions such as pre-eclampsia. However, little is known about the mechanisms underpinning vCT fusion. A new paper in Development demonstrates that the formation of microvilli on the apical surface of vCTs is crucial for fusion and the formation of the ST. To learn more about the story behind the paper, we caught up with first author Wendy Duan and corresponding author Meghan Riddell, Associate Professor at the University of Alberta, Canada.
Meghan Riddell (left) and Wendy Duan (right)
Meghan, what questions are your lab trying to answer?
MR: My lab is trying to understand how polarity is established and contributes to the differentiation and homeostasis of placental trophoblasts. We are particularly interested in polarity regulation in the giant multinucleate syncytiotrophoblast (ST) and its precursors, the villous cytotrophoblasts (vCTs), since the ST is fundamental to placental function. We also have questions we are pursuing about angiogenesis at the maternal-fetal interface and endothelial cell-driven processes that facilitate endometrial vascular reorganization in early pregnancy.
Wendy, how did you come to work in the lab and what drives your research today?
WD: When I first came into Dr Riddell's lab in 2023, it was mostly so that I would have a supervisor for my undergraduate honor's thesis. At the time, I was passably interested in reproductive physiology, even though I didn't have much knowledge on the subject. Luckily, she decided to give me a shot and throughout my undergraduate period I really ended up loving pregnancy research. Meghan also ended up liking me enough to allow me to continue my research in her lab. Currently I just love the research that we do here, the fact that our research can help further the field in such an understudied area, and working with the passionate, kind and uproariously funny lab-mates that I have here.
This work was inspired primarily by work in other fusing cell systems (myoblasts and oocyte/sperm), where membrane protrusions have been shown to play crucial regulatory roles in fusion
Tell us about the background of the field that inspired your work
MR & WD: This work was inspired primarily by work in other fusing cell systems (myoblasts and oocyte/sperm), where membrane protrusions have been shown to play crucial regulatory roles in fusion. We were very interested to understand if this is a conserved feature of all fusing cell types and would hold true for trophoblasts. Trophoblasts are an interesting fusing cell type because the fusogen, the protein that facilitates membrane fusion, has been known for many years. Since the discovery of the fusogen, there has been less investigation into the cell shape and biomechanics of trophoblast fusion compared with other fusing cells.
Can you give us the key results of the paper in a paragraph?
MR & WD: We found that microvilli are a key morphological feature shared by fusion-competent vCTs, the mononuclear progenitor cells that form the ST. Disrupting microvillar stability using ezrin inhibition disrupts vCT fusion, ST differentiation and polarized endocytosis in vCT progenitors. Interfering with the microvillar and apically polarized localization of a pro-fusogenic glycoprotein CD98 was also found to disrupt vCT fusion. Therefore, our data suggest that microvilli are key centers for coordinating pro-fusogenic signals in vCTs to facilitate effective ST development.
Microvilliated villous cytotrophoblasts on a 10.0 weeks gestational age placenta 24 h post-trypsinization. Imaged using scanning electron microscopy.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
WD: The most memorable moment for me was when I was imaging the placental explants with scanning electron microscopy. At that point, we had only seen what we thought were microvilli with confocal microscopy, and I had never done scanning electron microscopy before. I basically livestreamed my imaging session to Meghan, sending her every single picture that I took. Getting to zoom in and scan across the surface of the villi was incredible.
Why did you choose to submit this paper to Development?
MR & WD: We admire the open and inclusive policies for review and publishing at Development and The Company of Biologists, the high quality of work and the beautiful images that are published!
Wendy, what is next for you after this paper?
WD: I will continue to chug along in my PhD, although the second half of my thesis will be moving into the endometrium. Of course, the placenta microvilliation project remains close to my heart and I am always eager to hop back into the placenta world wherever I can.
Meghan, where will this story take your lab next?
MR: We will be continuing the work we started with this paper to understand what proteins are accumulating in vCT microvilli to support fusion and why their regionalization is important. We are also very interested to understand what regulates the polarized accumulation of microvilli in these cells. All our work in trophoblasts keeps emphasizing that they use interesting and unexpected interactions to achieve the same outcomes as other epithelia. So, it is certain to be a wild ride.
Finally, let's move outside the lab – what do you like to do in your spare time?
WD: I like to swim, play board games and play video games! I have also recently gotten into making miniatures and 3D wooden puzzles, even though those have been brutal on my wallet.
MR: I love to play in our beautiful Canadian Rocky Mountains. In the winter I cross-country ski and love backcountry skiing, while in the summer I enjoy hiking and mountain biking. Basically, any fun outside adventure I can do with my family!
W.D. & M.R.: Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
M.R.: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
E-mail: [email protected]
