Mütterlich-embryonales Übersprechen über Thrombozyten und EVs: ein neuer Mechanismus der embryonalen Umprogrammierung

• Antragsteller: Dr. Shrey Kohli
• Fachliche Zuordnung: Public Health, Gesundheitsbezogene Versorgungsforschung, Sozial- und Arbeitsmedizin ; Gynäkologie und Geburtshilfe
• Förderung: Förderung von 2018 bis 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 396257148

• Erstellungsjahr: 2023

Zusammenfassung der Projektergebnisse

Thrombo-inflammatory gestational vascular complications (TIGVCs) such as preeclampsia (PE) are associated with maternal and fetal morbidity and mortality. PE not only results in an inflammatory insult to maternal organs but also affects the embryos resulting in IUGR. This increases the risk for cardiovascular and metabolic diseases in the embryos later in life. The underlying in utero mechanisms and the mechanisms perpetuating the consequences into postnatal life remain under-studied. We have previously shown that maternal extracellular vesicles (EVs) promote preeclampsia by triggering a thrombo-inflammatory pathway at the feto-maternal interface. In particular, EVs cause platelet-activation, accumulation of activated platelets within the placenta, NLRP3 inflammasome activation in embryonic trophoblast cells. It remains unresolved as to what promotes accumulation of activated platelets predominantly in the placenta. Besides, the effects of EVs and activated platelets on the embryo proper and its consequences later in life remain unknown. In the current proposal we were able to identify a new function of placental thrombomodulin (TM), a coagulation regulator in PE and suggested that soluble TM limits thromboinflammatory pregnancy complications. Furthermore, we identified a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggested platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation. In follow-up studies we show that lowmolecular weight heparin (LMWH), a safe anticoagulant used during pregnancy is able to prevent inflammasome activation and restores trophoblast function. While LMWH is not indicated for preeclampsia, its potential anti-inflammatory effects suggest that further studies are required to explore its potential beneficial effects. Finally, we identified that EVs do not only induce a PE-like phenotype, but are causatively linked with re-programming of embryonic tissues such as heart, kidney and brain, which predisposes the mice to complications in adult life. Importantly, we observed that such offspring are biased towards an inflammatory state and more severe disease courses (e.g. in renal diseases) later in life. Further studies focusing on identifying the potential of resident immune-cell programming are required to outline mechanisms in detail.

Projektbezogene Publikationen (Auswahl)

• Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes. Communications Biology, 1(1).
  Shahzad, Khurrum; Gadi, Ihsan; Nazir, Sumra; Al-Dabet, Moh’d. Mohanad; Kohli, Shrey; Bock, Fabian; Breitenstein, Lukas; Ranjan, Satish; Fuchs, Tina; Halloul, Zuhir; Nawroth, Peter. P.; Pelicci, Pier Giuseppe; Braun-Dullaeus, Ruediger C.; Camerer, Eric; Esmon, Charles T. & Isermann, Berend
  
• Cell biology of activated protein C. Current Opinion in Hematology, 26(1), 41-50.
  Shahzad, Khurrum; Kohli, Shrey; Al-Dabet, Moh’d. Mohanad & Isermann, Berend
  
• Podocyte Integrin-β 3 and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy. Journal of the American Society of Nephrology, 31(8), 1762-1780.
  Madhusudhan, Thati; Ghosh, Sanchita; Wang, Hongjie; Dong, Wei; Gupta, Dheerendra; Elwakiel, Ahmed; Stoyanov, Stoyan; Al-Dabet, Moh’d. Mohanad; Krishnan, Shruthi; Biemann, Ronald; Nazir, Sumra; Zimmermann, Silke; Mathew, Akash; Gadi, Ihsan; Rana, Rajiv; Zeng-Brouwers, Jinyang; Moeller, Marcus J.; Schaefer, Liliana; Esmon, Charles T. ... & Isermann, Berend
  
• Crosstalk between inflammation and coagulation: Focus on pregnancy related complications. Thrombosis Update, 5, 100072.
  Kohli, Shrey & Isermann, Berend
  
• LMWH Prevents Platelet and Extracellular Vesicle Mediated Thrombo-inflammation in Preeclampsia. ISTH 2021
  Shrey Kohli; Kunal Singh; Anubhuti Gupta; Massimiliano Lia; Holger Stepan & Berend Isermann
  
• Maternal platelets pass interstices of trophoblast columns and are not activated by HLA-G in early human pregnancy. Journal of Reproductive Immunology, 144, 103280.
  Guettler, Jacqueline; Forstner, Désirée; Cvirn, Gerhard; Maninger, Sabine; Brugger, Beatrice A.; Nonn, Olivia; Kupper, Nadja; Pritz, Elisabeth; Wernitznig, Stefan; Dohr, Gottfried; Hutter, Heinz; Juch, Herbert; Isermann, Berend; Kohli, Shrey & Gauster, Martin
  
• Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression. Blood, 137(7), 977-982.
  Kohli, Shrey; Singh, Kunal Kumar; Gupta, Anubhuti; Markmeyer, Paulina; Lochmann, Franziska; Gupta, Dheerendra; Rana, Rajiv; Elwakiel, Ahmed; Huebner, Hanna; Ruebner, Matthias & Isermann, Berend
  
• Procoagulant Extracellular Vesicles Alter Trophoblast Differentiation in Mice by a Thrombo-Inflammatory Mechanism. International Journal of Molecular Sciences, 22(18), 9873.
  Markmeyer, Paulina; Lochmann, Franziska; Singh, Kunal Kumar; Gupta, Anubhuti; Younis, Ruaa; Shahzad, Khurrum; Biemann, Ronald; Huebner, Hanna; Ruebner, Matthias; Isermann, Berend & Kohli, Shrey
  
• Vaccine-Induced Thrombotic Thrombocytopenia: Insights from Blood Smear. Thrombosis and Haemostasis, 121(12), 1696-1698.
  Zimmermann, Silke; Federbusch, Martin; Isermann, Berend & Kohli, Shrey
  
• Activated Protein C Ameliorates Tubular Mitochondrial Reactive Oxygen Species and Inflammation in Diabetic Kidney Disease. Nutrients, 14(15), 3138.
  Rana, Rajiv; Manoharan, Jayakumar; Gupta, Anubhuti; Gupta, Dheerendra; Elwakiel, Ahmed; Khawaja, Hamzah; Fatima, Sameen; Zimmermann, Silke; Singh, Kunal; Ambreen, Saira; Gadi, Ihsan; Biemann, Ronald; Jiang, Shihai; Shahzad, Khurrum; Kohli, Shrey & Isermann, Berend
  
• Direct oral anticoagulants cause placental vascular abnormalities and epigenetic reprogramming in placenta and the offspring. ISTH 2022
  Kunal Singh Anubhuti Gupta; Ruaa Younis; Khurrum Shahzad; Berend Isermann & Shrey Kohli;
  
• ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis. Nutrients, 14(14), 2786.
  Fatima, Sameen; Ambreen, Saira; Mathew, Akash; Elwakiel, Ahmed; Gupta, Anubhuti; Singh, Kunal; Krishnan, Shruthi; Rana, Rajiv; Khawaja, Hamzah; Gupta, Dheerendra; Manoharan, Jayakumar; Besler, Christian; Laufs, Ulrich; Kohli, Shrey; Isermann, Berend & Shahzad, Khurrum
  
• Hypercoagulability Impairs Plaque Stability in Diabetes-Induced Atherosclerosis. Nutrients, 14(10), 1991.
  Ambreen, Saira; Fatima, Sameen; Elwakiel, Ahmed; Rana, Rajiv; Singh, Kunal; Gupta, Anubhuti; Gupta, Dheerendra; Khawaja, Hamzah; Manoharan, Jayakumar; Besler, Christian; Laufs, Ulrich; Kohli, Shrey; Isermann, Berend & Shahzad, Khurrum
  
• Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease. Nutrients, 14(14), 2965.
  Gupta, Anubhuti; Singh, Kunal; Fatima, Sameen; Ambreen, Saira; Zimmermann, Silke; Younis, Ruaa; Krishnan, Shruthi; Rana, Rajiv; Gadi, Ihsan; Schwab, Constantin; Biemann, Ronald; Shahzad, Khurrum; Rani, Vibha; Ali, Shakir; Mertens, Peter Rene; Kohli, Shrey & Isermann, Berend
  
• Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression. Nature Communications, 13(1).
  Al-Dabet, Moh’d. Mohanad; Shahzad, Khurrum; Elwakiel, Ahmed; Sulaj, Alba; Kopf, Stefan; Bock, Fabian; Gadi, Ihsan; Zimmermann, Silke; Rana, Rajiv; Krishnan, Shruthi; Gupta, Dheerendra; Manoharan, Jayakumar; Fatima, Sameen; Nazir, Sumra; Schwab, Constantin; Baber, Ronny; Scholz, Markus; Geffers, Robert; Mertens, Peter Rene ... & Isermann, Berend
  
• Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C. Frontiers in Cardiovascular Medicine, 9.
  Kohli, Shrey; Shahzad, Khurrum; Jouppila, Annukka; Holthöfer, Harry; Isermann, Berend & Lassila, Riitta
  
• Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-ketoglutarate. Blood Advances, 7(17), 5055-5068.
  Gupta, Dheerendra; Elwakiel, Ahmed; Ranjan, Satish; Pandey, Manish Kumar; Krishnan, Shruthi; Ambreen, Saira; Henschler, Reinhard; Rana, Rajiv; Keller, Maria; Ceglarek, Uta; Shahzad, Khurrum; Kohli, Shrey & Isermann, Berend
  
• CD248 induces a maladaptive unfolded protein response in diabetic kidney disease. Kidney International, 103(2), 304-319.
  Krishnan, Shruthi; Manoharan, Jayakumar; Wang, Hongjie; Gupta, Dheerendra; Fatima, Sameen; Yu, Yanfei; Mathew, Akash; Li, Zhen; Kohli, Shrey; Schwab, Constantin; Körner, Antje; Mertens, Peter R.; Nawroth, Peter; Shahzad, Khurrum; Naumann, Michael; Isermann, Berend & Biemann, Ronald
  
• Platelet hyperactivation and neutrophil extracellular traps promote thrombo-inflammation and glomerular endothelial dysfunction in diabetic kidney disease. Hämostaseologie, 43. Georg Thieme Verlag.
  Gupta, A.; Singh, K. K.; Fatima, S.; Ambreen, S.; Zimmermann, S.; Isermann, B. & Kohli, S.
  
• Glomerular-tubular crosstalk via cold shock Y-box binding protein-1 in the kidney. Kidney International, 105(1), 65-83.
  Rana, Rajiv; Manoharan, Jayakumar; Elwakiel, Ahmed; Zimmermann, Silke; Lindquist, Jonathan A.; Gupta, Dheerendra; Al-Dabet, Moh'd. Mohanad; Gadi, Ihsan; Fallmann, Jörg; Singh, Kunal; Gupta, Anubhuti; Biemann, Ronald; Brandt, Sabine; Alo, Bekas; Kluge, Paul; Garde, Ravindra; Lamers, Christina; Shahzad, Khurrum; Künze, Georg ... & Isermann, Berend