The effects of rare damaging mutations in TGFb latent complex proteins found in preeclamptic placentas 9400

Abstract Description Preeclampsia (PE) complicates 8% of pregnancies globally, causing over 50,000 maternal and 500,000 fetal deaths annually. Characterized by hypertension, PE results from poor placental development, partly due to impaired extravillous trophoblast (EVT) differentiation and invasion. Transforming growth factor-beta (TGFβ) signaling, crucial for trophoblast function, regulates cell migration and extracellular matrix (ECM) remodeling. Dysregulated TGFβ signaling, including elevated TGFβ levels in preeclamptic placentas, disrupts these processes, leading to placental dysfunction and adverse outcomes. Our research identifies rare damaging mutations in TGFβ latent complex proteins, including Fibronectin 1 (FN1) and Latent Transforming Growth Factor Beta Binding Protein 1 (LTBP1), in placentas and umbilical cord-derived mesenchymal stem cells (MSCs) from PE-affected pregnancies. We hypothesize these mutations impair TGFβ latency, enhancing active signaling and disrupting ECM integrity, ultimately affecting EVT migration, invasion and differentiation. Analysis of MSCs from PE and normotensive pregnancies shows increased FN1 protein expression in mutant MSCs (p = 0.035) but no change in total TGFβ secretion (p = 0.959). Next, we will examine how the mutations alter TGFβ signaling and downstream signals. Insights could inform diagnostic tools, therapies, and preventive strategies for PE and placental disorders involving TGFβ and ECM dysfunction, improving maternal and fetal health outcomes. Funding Sources Supported by K12GM068524 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)