Syncytiotrophoblast differentiation defects drive ER stress and reprogram placental PSG1 glycosylation in preeclampsia
17 affiliations
- 1Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 2Glyco-HAM, a Cooperation of Universität Hamburg, Technology Platform Mass Spectrometry and University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 3Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA.
- 4Global Development CMC Biologicals, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an Der Riss, Germany.
- 53D Tissue Bioprinting Laboratory, National Center for Advancing Translational Sciences, National Institute of Sciences, Bethesda, MD, USA.
- 6Human Health Therapeutics, National Research Council Canada, Ottawa, ON, Canada.
- 7Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
- 8Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany.
- 9Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
- 10Department of Obstetrics and Gynecology, School of Medicine, Semmelweis University, Budapest, Hungary.
- 11Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary.
- 12Genesis Theranostix Group, Budapest, Hungary.
- 13Experimental and Clinical Research Center, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité - Universitätsmedizin Berlin, Berlin, Germany.
- 14Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
- 15Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA. [email protected].
- 16Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
- 17Glyco-HAM, a Cooperation of Universität Hamburg, Technology Platform Mass Spectrometry and University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
Abstract
During pregnancy, placenta-derived proteins such as pregnancy-specific glycoprotein 1 (PSG1) enter the maternal circulation, providing a window into placental health and enabling liquid biopsy strategies for monitoring pregnancy disorders. PSG1, a highly glycosylated protein secreted by syncytiotrophoblast (STB) cells, reflects trophoblast differentiation status. Circulating PSG1 levels are reduced in early-onset preeclampsia (PE), but how PSG1 glycosylation is altered in this condition remains unclear. Here, we show by liquid chromatography-tandem mass spectrometry that native PSG1 purified from healthy and early-onset PE pregnancies carries an O-linked glycan in its N domain in addition to diverse N-linked glycans. In PE, PSG1 N-glycans displayed a shift toward increased oligomannose structures and reduced sialylation. Induction of endoplasmic reticulum (ER) stress in primary STBs altered the glycosylation enzyme machinery, and single-nucleus transcriptomic data indicated a reduced contribution of mature STB populations in PE, consistent with an immature STB-like glycoprotein signature. Altered N-glycosylation increased binding to mannose and asialoglycoprotein receptors and cellular uptake, suggesting enhanced hepatic clearance as a possible explanation for reduced circulating PSG1 levels in PE. Our data link ER stress during STB differentiation to altered glycoprotein maturation and identify PSG1 glycosylation as a readout of a stress-impaired STB in PE. Glycan features of circulating placental proteins could therefore provide information beyond protein levels alone and complement liquid biopsy approaches.
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BibTeX
@article{harms2026syncytiotrophoblast,
title = {{Syncytiotrophoblast differentiation defects drive ER stress and reprogram placental PSG1 glycosylation in preeclampsia}},
author = {Charlotte Harms and Yiru Wang and James Warren and Julia Baumeister and Fabian Higel and Cristina Antich and Marc Ferrer and Jennifer J Hill and Mariana G Garcia and Alexandra Gellhaus and Nándor Gábor Than and Florian Herse and Stefan Verlohren and Gabriela S Dveksler and Sandra M Blois},
journal = {Molecular Biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00634-x},
url = {https://doi.org/10.1186/s43556-026-00634-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - Syncytiotrophoblast differentiation defects drive ER stress and reprogram placental PSG1 glycosylation in preeclampsia
AU - Charlotte Harms
AU - Yiru Wang
AU - James Warren
AU - Julia Baumeister
AU - Fabian Higel
AU - Cristina Antich
AU - Marc Ferrer
AU - Jennifer J Hill
AU - Mariana G Garcia
AU - Alexandra Gellhaus
AU - Nándor Gábor Than
AU - Florian Herse
AU - Stefan Verlohren
AU - Gabriela S Dveksler
AU - Sandra M Blois
PY - 2026
DA - 2026/10/01
JO - Molecular Biomedicine
DO - 10.1186/s43556-026-00634-x
UR - https://doi.org/10.1186/s43556-026-00634-x
AB - During pregnancy, placenta-derived proteins such as pregnancy-specific glycoprotein 1 (PSG1) enter the maternal circulation, providing a window into placental health and enabling liquid biopsy strategies for monitoring pregnancy disorders. PSG1, a highly glycosylated protein secreted by syncytiotrophoblast (STB) cells, reflects trophoblast differentiation status. Circulating PSG1 levels are reduced in early-onset preeclampsia (PE), but how PSG1 glycosylation is altered in this condition remains unclear. Here, we show by liquid chromatography-tandem mass spectrometry that native PSG1 purified from healthy and early-onset PE pregnancies carries an O-linked glycan in its N domain in addition to diverse N-linked glycans. In PE, PSG1 N-glycans displayed a shift toward increased oligomannose structures and reduced sialylation. Induction of endoplasmic reticulum (ER) stress in primary STBs altered the glycosylation enzyme machinery, and single-nucleus transcriptomic data indicated a reduced contribution of mature STB populations in PE, consistent with an immature STB-like glycoprotein signature. Altered N-glycosylation increased binding to mannose and asialoglycoprotein receptors and cellular uptake, suggesting enhanced hepatic clearance as a possible explanation for reduced circulating PSG1 levels in PE. Our data link ER stress during STB differentiation to altered glycoprotein maturation and identify PSG1 glycosylation as a readout of a stress-impaired STB in PE. Glycan features of circulating placental proteins could therefore provide information beyond protein levels alone and complement liquid biopsy approaches.
SN - 2662-8651
ER -