Exosomal MicroRNA-325 Enhances Trophoblast Migration and Invasion Through Downregulation of Lethal-7b and Upregulation of Forkhead Box Protein O1 Expression in Preeclampsia

Abstract

We aimed to explore the mechanism by how microRNA (miRNA)-325 derived from marrow mesenchymal stem cell exosomes (MSC-exos) affects the trophoblast progression in preeclampsia (PE). RT-qPCR detected the level of miRNA let-7b and FOXO1 in the placenta tissue of PE patients. Functional experiment was performed to analyze the effect of FOXO1 inhibitor and let-7b mimics on cell migration, invasion and apoptosis through Transwell assay and TUNEL staining. The trophoblast cell was co-cultured with overexpressed-miR-325 MSC-exos to measure gene expression and cell progression. let-7b was highly and FOXO1 was lowly expressed in PE placenta tissue. let-7b directly targeted and inhibited FOXO1 expression. Importantly, as miR-325 was internalized by trophoblast cells through MSC-exos, MSC-exos overexpressing miR-325 inhibited let-7b expression in trophoblasts, up-regulated FOXO1 and activated AKT signaling pathway. Further, MSC-exos treatment promoted invasion and migration of trophoblast cell and inhibited apoptosis. In conclusion, miR-325 derived from MSC-exos promotes the invasion and migration of trophoblast cells in PE through inhibition of let7b and upregulation of FOXO1.

Mesenchymal stem cell‐derived exosomes in preeclampsia: A next‐generation therapeutic tool

“…In conclusion, miR-325 derived from MSC-exosome stimulates FOXO1 upregulation and let7b inhibition to enhance trophoblast cell invasion and migration in PE. 155 A summary of the therapeutic utility of MSCs-exosome for PE therapy has been offered in Table 4.…”

“…Human umbilical cord miR-139-5p ERK/MMP-2 Speed up trophoblast cell invasion and migration while inhibiting apoptosis [141] Amnion EZH2 mTOR Increased autophagy in hypoxic trophoblasts [146] Bone marrow miR-141 MALAT1-201 Controlled the migration, apoptosis, and proliferation of trophoblast cells [148] Human umbilical cord TFCP2 Wnt/β-catenin Enhances the growth dynamics and lowers EVT apoptosis [151] Human umbilical cord let-7b FOXO1 Targeting AKT signaling pathway [154] Bone marrow miR-325 FOXO1 Trophoblast cell invasion and migration [155] Abbreviations: EZH2, enhancer of zeste homolog 2; FOXO1, forkhead box O1; FSTL3, follistatin-like 3; MMP-2, matrix metalloproteinase-2; PDCD4, programmed cell death 4; sFlt-1, soluble fms-like tyrosine kinase-1; SCG2, secretogranin II; TFCP2, transcription factor cellular promoter 2; TFPI2, tissue factor pathway inhibitor 2; VEGF, vascular endothelial growth factor. Attempts to establish guidelines regarding the safety and efficacy of exosome therapy will hasten clinical utilization of MSC-derived exosomes as an intriguing therapeutic for PE.…”

“…Additionally, the administration of MSC‐exosome facilitated trophoblast cell invasion and migration while suppressing apoptosis. In conclusion, miR‐325 derived from MSC‐exosome stimulates FOXO1 upregulation and let7b inhibition to enhance trophoblast cell invasion and migration in PE 155 . A summary of the therapeutic utility of MSCs‐exosome for PE therapy has been offered in Table 4.…”

A comprehensive insight into the immunomodulatory role of MSCs‐derived exosomes (MSC‐Exos) through modulating pattern‐recognition receptors (PRRs)

“…The presence of miR-let-7b within MSC-Exos have been documented, indicating a prospective role in regulating TLR4-mediated responses. 73,74 Studies have indicated that miR-199a-5p has the ability to target TLR4 and diminish its expression. MSC-Exos harboring this particular miRNA could influence TLR4 signaling and the resultant immune response.…”

“…MiR‐let‐7b is recognized for its capacity to target TLR4 and curtail its expression. The presence of miR‐let‐7b within MSC‐Exos have been documented, indicating a prospective role in regulating TLR4‐mediated responses 73,74 …”