Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Forstner, D.
Effect of maternal platelets on trophoblasts.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 96
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gauster Martin
- Heinemann Akos
- Huppertz Berthold
- Altmetrics:
- Abstract:
- In early stage of pregnancy, a sequence of complex and tightly regulated processes guarantees the development of the placenta. Cytotrophoblast cells differentiate according to their functions at the fetal-maternal interface and extravillous trophoblasts invade into the maternal uterine arteries. The vessels are plugged to prevent maternal blood flow to reach the intervillous space in very early stages of pregnancy. Maternal blood plasma ultrafiltrate can pass the trophoblast plug to nourish the growing fetus. Immunohistochemical analysis of first trimester placental tissue revealed adherent maternal platelets in the intervillous space from very early stages of gestation. Maternal platelets may be the first cells to enter the intervillous space through intertrophoblastic gaps, when trophoblast plugs become loosely cohesive. Platelet adherence and thus also activation in the intervillous space, as an event in health and disease, may contribute to early placental development, as they provide a source of inflammatory mediators. Increased activation of aggregated platelets at the fetal-maternal interface is implicated in serious pregnancy pathologies, such a preeclampsia. In order to elucidate the influence of platelet-derived factors on trophoblast differentiation and endocrinology, first trimester placenta villi and the trophoblast cell line BeWo were incubated with platelet-derived factors, and subsequently analyzed by gene expression analysis, protein analysis, immunohistochemistry and scanning electron microscopy. The expression and synthesis of the beta-subunit of the human chorionic gonadotropin (hCG) in placental explants as well as in BeWo cells, were significantly downregulated due to stimulation with platelet-derived factors. Analysis of trophoblast fusion and differentiation markers showed that the downregulation of βhCG is not a consequence of hampered differentiation per se. Smad3 and its downstream-target plasminogen activator inhibitor (PAI)-1 was strongly activated after treatment with platelet-derived factors. Due to the usage of TGF-β/Smad inhibitors and an inhibitor for co-activator complex CBP/p300, our study suggests an interference of differentiation-induced cAMP/CREB signaling pathway and Smad3 signaling. Sequestration of transcription co-activators CBP/p300, known to bind both CREB and Smad3, may limit βhCG production. In conclusion, this thesis will contribute to a deeper understanding of trophoblast differentiation under consideration of platelet activation in the intervillous space in early pregnancy.