Exosomal microRNA-139-5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP-2 pathway via downregulation of protein tyrosine phosphatase

Aim: Exosomes present essential roles for intercellular interaction via extracellular pathways during systemic dysfunctions, including preeclampsia (PE). Here, we assessed the specific mechanism of mesenchymal stem cells (MSC)-originated exosomes in PE.

Methods: The effects of exosomes on trophoblasts were studied by EdU, wound healing, Transwell and TUNEL assays. By microarray analysis, we found that exosomes enhanced the microRNA-139-5p (miR-139-5p) in trophoblasts, and confirmed the target gene of miR-139-5p by bioinformatics prediction and dual-luciferase reporter gene assay. At the same time, ERK/MMP-2 pathway-related biomolecules were assessed through Western blot analysis. The pathway inhibitor was used for rescue experiments. Finally, the effect of exosomes on the pathology of PE rats was verified by in vivo experiments.

Results: The exosomes originated from hucMSC fostered the trophoblast cell migration, invasion and proliferation and obstructed Apoptosis. Moreover, miR-139-5p could be transmitted to trophoblasts through hucMSC-secreted exosomes. miR-139-5p targeted protein tyrosine Phosphatase (PTEN), which regulated the ERK/MMP-2 pathway. Inhibition of the ERK/MMP-2 pathway significantly reduced the promoting effect of exosomes on trophoblasts. Treatment with exosomes significantly lowered blood pressure values and reduced 24-h proteinuria in PE rats.

Conclusion: hucMSC-originated exosomes overexpressing miR-139-5p activated the ERK/MMP-2 pathway via PTEN downregulation, thus accelerating trophoblast cell invasion and migration, and blocking Apoptosis. These results demonstrated that hucMSC-derived exosomes overexpressing miR-139-5p might be an innovative direction for therapeutic approaches against PE.