Exosomal THBS4 Derived From Human Placental Mesenchymal Stem Cells Promotes the Migration and Angiogenesis of the Endothelial Cells in Preeclampsia by Activating the Integrin α2/PI3K/AKT Axis

Introduction: Preeclampsia (PE) is a pregnancy-specific disease with limited treatment options. Although human placental mesenchymal stem cells (hPMSCs) hold therapeutic potential, their clinical use faces safety and practical challenges. Placental mesenchymal stem cell exosomes (PMSC-Exos) offer a promising cell-free alternative. We hypothesized that PMSC-Exos may effectively alleviate PE and investigated the underlying molecular mechanisms. Methods: Exosomes derived from hPMSCs were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, Western blotting (WB), and nanoparticle flow cytometry. Proteomic profiling compared PMSC and exosome protein profiles. THBS4 expression was assessed in healthy and PE placental tissues using quantitative real-time PCR, WB, and immunohistochemistry (IHC). The effects of PMSC-Exos on endothelial cells were examined by exosome uptake assay, transwell migration assay, tube formation assay, immunofluorescence, and Western blotting. In a rat PE model, PMSC-Exos were administered via intraplacental injection. Therapeutic outcomes were assessed by measuring systolic blood pressure, urinary protein levels, and analyzing placental and renal tissues with Hematoxylin and Eosin staining, IHC, and WB. Results: We successfully isolated and characterized PMSC-Exos, which were enriched with THBS4 compared to PMSCs. THBS4 expression was downregulated in preeclamptic versus healthy placental tissues. In vitro experiments demonstrated that THBS4 contained in PMSC-Exos bound to integrin α 2 (ITG α 2) on endothelial cells, leading to the activation of the PI3K/AKT signaling pathway and enhanced endothelial cell migration and angiogenic function. In vivo, administration of PMSC-Exos alleviated PE symptoms, improved placental structure, and supported fetal growth. Conclusion: These findings demonstrate that PMSC-Exos promote vascular endothelial cell migration and angiogenesis through the THBS4/integrin α 2/PI3K/AKT axis, leading to improved pregnancy outcomes in a rat model of PE. THBS4 may serve as a key therapeutic target for preeclampsia. This proof-of-concept study supports the therapeutic potential of PMSC-Exos, pending further translational research. Keywords: thrombosponding-4, mesenchymal stem cell, exosomes, endothelial cells, preeclampsia, placenta