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.

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).

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