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

Abstract

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 dualluciferase 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.

Exosomal miR-486-5p derived from human placental microvascular endothelial cells regulates proliferation and invasion of trophoblasts via targeting IGF1

“…Previous research has confirmed that exosomes play a role in multiple conditions, including PE [11,25,26]. Furthermore, trophoblast cell growth inhibition, and dysregulation of miRNAs are involved in the progression of PE [27,28]. In the current study, we found that the growth of trophoblast cells was significantly inhibited by miR-486-5p inhibitor carried by HPVEC-exo.…”

Human Umbilical Cord Mesenchymal Stem Cell (HUCMSC)-derived Exosomes as a Cell-Free Therapy for Soluble Fms-like Tyrosine Kinase-1 (Sflt-1)-induced Endothelial Dysfunction in Preeclampsia

“…Due in part to studying the paracrine effects of stem cell therapy, this speci c therapy has been mechanistically linked to the inherited functions of secreting exosomes [24]. Recently, research suggested HUCMSC-originated exosomes might be an innovative direction for therapeutic approaches against PE by accelerating trophoblast cell invasion and migration [21,25].…”

“…Compared with HUCMSCs, the up-expressed proteins in HUCMSCexos were MMP2 (Matrix metalloproteinase 2, fold change = 14.7) and VCAN (versican, fold change = 11.7). Previous study showed that MSC-exo could promote the migration of endothelium cells by delivering MMP2 [21]. VCAN contributes to tissue development and maintenance by participating in cell adhesion, proliferation and angiogenesis via binding to ECM components [22].…”

Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions

“…From the four studies shown in Table 1 on testing MSC-derived EVs in models of preeclampsia, two were in vitro studies performed using HUVECs [ 159 ] or trophoblasts [ 160 ] as cell models, while the other two were in vivo studies performed in rat models of preeclampsia [ 161 , 162 ]. EVs derived from human decidua MSCs were found to enhance HUVEC proliferation by reducing inflammation and oxidative stress [ 159 ].…”

“…The two studies that performed in vivo testing to investigate the effects of MSC-derived EVs in rat models of preeclampsia both used human umbilical cord MSCs as the cell source for producing EVs. One study using exosomes from the MSCs showed that these significantly lowered blood pressure and proteinuria in the animal model, both key features of preeclampsia [ 161 ]. From in vitro experiments performed in the same study, it was noted that the exosomes could promote trophoblast cell migration, invasion and proliferation while reducing apoptosis, possibly by transferring miR-139-5p to the trophoblasts and thereby regulating the ERK/MMP-2 pathway.…”