The syncytiotrophoblast is a single giant multinucleate epithelial cell that forms the maternal surface of the human placenta and is bathed in maternal blood. It acts as a physical barrier between the maternal and fetal compartments and facilitates nutrient and waste exchange. As such, syncytiotrophoblast dysfunction is a key feature of pregnancy pathologies, such as preeclampsia. An understudied feature of dysfunctional syncytiotrophoblast is the loss of apical microvilli. But a paucity of data exists about the mechanisms regulating syncytiotrophoblast microvilli maintenance. Atypical protein kinase-c (aPKC) isoforms are evolutionarily conserved apical polarity regulators, which are known to play a role in the regulation of intestinal microvilli. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast microvilli and apical surface structure. Using human placental explant culture and primary human trophoblasts, we found that aPKCs regulate the structure, permeability, and endocytic function of the syncytiotrophoblast apical surface in a spatially restricted manner.
A heightened inflammatory environment is often involved in the pathogenesis of placental pathologies, and the pro-inflammatory cytokine TNF-α can decrease aPKC-ι expression in intestinal cells. Here we establish that TNF-α exposure leads to reduced expression of the aPKC-ι isoform in syncytiotrophoblast and profoundly alters ST apical structure and permeability via regionalized pyroptosis, a highly pro-inflammatory form of cell death. Therefore, this is the first work to identify a regulator of apical-surface structure and the induction of the pyroptotic cascade at the maternal surface of the human placenta.
The syncytiotrophoblast is a human epithelial cell that is bathed in
maternal blood on the maternal-facing surface of the human placenta. It
therefore acts as a barrier and exchange interface between the mother and
fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy
pathologies, like preeclampsia. Dysfunctional syncytiotrophoblasts display a
loss of microvilli, which is a marker of aberrant apical–basal polarization,
but little data exist about the regulation of syncytiotrophoblast polarity.
Atypical PKC isoforms are conserved polarity regulators. Thus, we
hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using
human placental explant culture and primary trophoblasts, we found that loss
of aPKC activity or expression induces syncytiotrophoblast
gasdermin-E-dependent pyroptosis, a form of programmed necrosis. We also
establish that TNF-α induces an isoform-specific decrease in aPKC expression
and gasdermin-E-dependent pyroptosis. Therefore, aPKCs are homeostatic
regulators of the syncytiotrophoblast function and a pathogenically relevant
pro-inflammatory cytokine leads to the induction of programmed necrosis at
the maternal–fetal interface. Hence, our results have important implications
for the pathobiology of placental disorders like preeclampsia.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.