# Deficient extravillous trophoblast invasion caused by impaired sialylation–Siglec-7 interaction contributes to recurrent pregnancy loss

## TL;DR

The study finds that reduced sialylation in trophoblast cells disrupts immune signaling, leading to impaired cell invasion and contributing to recurrent pregnancy loss.

## Contribution

The paper identifies a novel sialic acid–Siglec-7–IL-8–STAT3 signaling axis critical for trophoblast invasion and disrupted in recurrent pregnancy loss.

## Key findings

- Reduced sialylation in RPL patients correlates with increased Siglec-7⁺ decidual NK cells.
- Sialylation restoration rescues IL-8–STAT3 signaling and trophoblast invasiveness.
- Defective sialylation disrupts a key immunological checkpoint for healthy pregnancy.

## Abstract

Successful pregnancy requires precise immune interactions between fetal extravillous trophoblasts (EVT) and maternal decidual immune cells at the maternal–fetal interface. Glycosylation, particularly terminal sialylation, is emerging as a key modulator of these interactions; however, its functional role in regulating the EVT–immune crosstalk remains poorly defined. Here, we aimed to identify a critical sialic acid–Siglec-7–IL-8–STAT3 signaling axis that promotes EVT invasiveness and is disrupted during recurrent pregnancy loss (RPL). Using primary human tissues and organ-on-chip models, we demonstrate that EVTs from patients with RPL exhibit reduced sialylation, coinciding with an increased proportion of Siglec-7⁺ decidual natural killer (dNK) cells. Mechanistically, sialylated glycoproteins on EVT surfaces engage Siglec-7, stimulating IL-8 secretion by dNK cells, which, in turn, activates STAT3 in EVTs to enhance migration and invasion. Restoration of EVT sialylation re-engages Siglec-7, rescues IL-8–STAT3 signaling, and restores invasive capacity. Our findings reveal that defective EVT sialylation disrupts a key immunological checkpoint that normally promotes EVT invasion and potentially contributes to RPL. This work provides direct mechanistic evidence that specific glycan-encoded immune signals at the maternal-fetal interface are critical for healthy pregnancy outcomes and suggests that modulating sialylation may offer a therapeutic strategy for RPL.

Proposed model of sialic acid–Siglec-7–mediated regulation of EVT invasion through the ST6GALNAC6–sialic acid–Siglec-7–IL-8–STAT3 signaling axis. Schematic representation of the working model: enhanced sialylation of EVT membrane glycoproteins—driven by ST6GALNAC6—facilitates recognition by Siglec-7 expressed on dNK cells. This interaction promotes the activation of the IL-8–STAT3 signaling pathway, which supports EVT cell migration and invasion. Disruption of sialylation or Siglec-7 engagement impairs this pathway and reduces EVT invasiveness, potentially contributing to the pathogenesis of RPL. Figure created with BioRender.com (https://BioRender.com/dxxt5az).

Proposed model of sialic acid–Siglec-7–mediated regulation of EVT invasion through the ST6GALNAC6–sialic acid–Siglec-7–IL-8–STAT3 signaling axis. Schematic representation of the working model: enhanced sialylation of EVT membrane glycoproteins—driven by ST6GALNAC6—facilitates recognition by Siglec-7 expressed on dNK cells. This interaction promotes the activation of the IL-8–STAT3 signaling pathway, which supports EVT cell migration and invasion. Disruption of sialylation or Siglec-7 engagement impairs this pathway and reduces EVT invasiveness, potentially contributing to the pathogenesis of RPL. Figure created with BioRender.com (https://BioRender.com/dxxt5az).