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Research Article
Originally Published 23 October 2024
Open Access

Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia

Olivia Nonn https://orcid.org/0000-0001-6385-2866, Olivia Debnath, Daniela S. Valdes https://orcid.org/0000-0002-1309-5147, Katja Sallinger, Ali Kerim Secener https://orcid.org/0000-0003-4806-2852, Cornelius Fischer https://orcid.org/0000-0003-0329-2435, Sebastian Tiesmeyer https://orcid.org/0000-0002-0492-1523, Show All , Jose Nimo https://orcid.org/0000-0002-1565-7799, Thomas Kuenzer https://orcid.org/0000-0001-6882-1217, Juliane Ulrich, Theresa Maxian https://orcid.org/0000-0002-8009-8479, Martin Knöfler, Philipp Karau https://orcid.org/0000-0001-6590-1975, Hendrik Bartolomaeus https://orcid.org/0000-0003-4288-3828, Thomas Kroneis https://orcid.org/0000-0002-4761-9340, Alina Frolova https://orcid.org/0000-0001-5469-7366, Lena Neuper, Nadine Haase, Alexander Malt, Niklas Müller-Bötticher https://orcid.org/0000-0001-5103-7282, Kristin Kräker https://orcid.org/0000-0002-4032-5382, Sarah Kedziora https://orcid.org/0000-0003-0124-2557, Désirée Forstner https://orcid.org/0000-0001-5451-7580, Roland Eils, Ruth Schmidt-Ullrich https://orcid.org/0000-0002-2472-6530, Sandra Haider https://orcid.org/0000-0003-2409-1317, Stefan Verlohren https://orcid.org/0000-0003-3507-8636, Christina Stern https://orcid.org/0000-0002-6330-1236, Meryam Sugulle https://orcid.org/0000-0003-4160-3978, Stuart Jones https://orcid.org/0000-0002-3106-6155, Basky Thilaganathan https://orcid.org/0000-0002-5531-4301, Tu’uhevaha J. Kaitu’u-Lino https://orcid.org/0000-0001-6233-9737, Stephen Tong, Berthold Huppertz https://orcid.org/0000-0003-4814-2158, Amin El-Heliebi https://orcid.org/0000-0002-7679-6856, Anne Cathrine Staff https://orcid.org/0000-0001-9247-5721, Fabian Coscia https://orcid.org/0000-0002-2244-5081, Dominik N. Müller, Ralf Dechend https://orcid.org/0000-0001-6636-3080, Martin Gauster https://orcid.org/0000-0003-0386-6857, Naveed Ishaque https://orcid.org/0000-0002-8426-901X, and Florian Herse https://orcid.org/0000-0002-9305-8134 [email protected]Author Info & Affiliations

Abstract

BACKGROUND:

Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce.

METHODS:

To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation.

RESULTS:

We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis.

CONCLUSIONS:

This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

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Hypertension
PubMed: 39440423

History

Received: 22 May 2024
Accepted: 7 October 2024
Published online: 23 October 2024

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Keywords

  1. placenta
  2. plasminogen activator inhibitor 1
  3. preeclampsia
  4. pregnancy
  5. pregnancy trimester, first

Subjects

Authors

Affiliations

Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Olivia Debnath*
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Katja Sallinger
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Centre for Biomarker Research in Medicine, Graz, Austria (K.S., T. Kroneis, A.E.-H.).
Institute for Medical Systems Biology (BIMSB), Berlin, Germany (A.K.S., C.F.).
Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany (A.K.S.).
Institute for Medical Systems Biology (BIMSB), Berlin, Germany (A.K.S., C.F.).
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria. (T. Kuenzer)
Juliane Ulrich
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Austria (T.M., M.K., S.H.).
Martin Knöfler
Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Austria (T.M., M.K., S.H.).
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Centre for Biomarker Research in Medicine, Graz, Austria (K.S., T. Kroneis, A.E.-H.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
Institute of Molecular Biology and Genetic of NASU, Kyiv, Ukraine (A.F.).
Lena Neuper
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Nadine Haase
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Alexander Malt
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Niklas Müller-Bötticher https://orcid.org/0000-0001-5103-7282
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Roland Eils
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Austria (T.M., M.K., S.H.).
Department of Obstetrics and Gynaecology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (S.V.).
Department of Obstetrics and Gynaecology, University Hospital Graz, Medical University Graz, Austria (C.S.).
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway (M.S., A.C.S.).
Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway (M.S., A.C.S.).
Clinical Biochemistry, King George’s Hospital, London, United Kingdom (S.J.).
Fetal Medicine Unit, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom (B.T.).
Tu’uhevaha J. Kaitu’u-Lino https://orcid.org/0000-0001-6233-9737
Department of Obstetrics and Gynaecology (Mercy Hospital for Women), The University of Melbourne, VIC, Australia (T.J.K.-L., S. Tong).
Stephen Tong
Department of Obstetrics and Gynaecology (Mercy Hospital for Women), The University of Melbourne, VIC, Australia (T.J.K.-L., S. Tong).
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Centre for Biomarker Research in Medicine, Graz, Austria (K.S., T. Kroneis, A.E.-H.).
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway (M.S., A.C.S.).
Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway (M.S., A.C.S.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
Dominik N. Müller
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).
German Center for Cardiovascular Research (DZHK), Berlin, Germany (O.N., D.S.V., H.B., N.H., K.K., S.K., D.N.M., R.D.).
Department of Cardiology and Nephrology, HELIOS Clinic, Berlin, Germany (R.D.).
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria. (O.N., K.S., T. Kroneis, L.N., D.F., B.H., A.E.-H., M.G.)
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center of Digital Health, Germany (O.D., S. Tiesmeyer, P.K., A.M., N.M.-B., R.E., N.I.).
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (O.N., D.S.V., J.N., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., F.C., D.N.M., R.D., F.H.).

Notes

*
O. Nonn, O. Debnath, and D.S. Valdes contributed equally.
N. Ishaque and F. Herse co-supervised this work.
For Sources of Funding and Disclosures, see page XXX.
Supplemental Material is available at Supplemental Material.
Correspondence to: Florian Herse, Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, Robert-Rössle-Straße 10, 13125 Berlin, Germany. Email [email protected]

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