Loss of polarity regulators initiates gasdermin E mediated pyroptosis in human maternal fetal interface trophoblasts

Abstract

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.

Placental cytotrophoblast microvillar stabilization is required for cell-cell fusion

“…Consistent with the findings in our in vitro model, anti-ezrin signal variably localized to the apical surface of individual vCT and, as previously reported, in a discontinuous pattern at the apical surface of the ST (Fig. 3C) (Berryman et al, 1993; Patel et al, 2023). Therefore, we confirmed that apical microvilli are present in a subset of vCT in the first trimester placenta.…”