MSC-Secreted Exosomal H19 Promotes Trophoblast Cell Invasion and Migration by Downregulating let-7b and Upregulating FOXO1

Abstract

Exosomes perform important functions for intercellular communication through extracellular signaling pathways, leading to the regulation of important biological processes, including cell proliferation, but also systemic dysfunctions such as preeclampsia (PE). However, the inhibitory effects of mesenchymal stem cell (MSCs)-derived exosomes in PE remain largely unknown. Thus, we assessed the possibility that exosomes could transport long non-coding RNA H19 and the correlation between H19 and the apoptosis of trophoblast cells. The expression of microRNA let-7b and forkhead box protein O1 (FOXO1) was characterized in placental tissues of PE patients. Gain-and lossof-function experiments were performed to examine the roles of FOXO1 and let-7b in trophoblast cells. Interactions between let-7b and H19 as well as between let-7b and FOXO1 were confirmed by a dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation. HTR-8/SVneo cells were co-cultured with exosomes derived from MSCs overexpressing H19, followed by invasion, migration, and apoptosis assessments of trophoblast cells. We found that let-7b was highly expressed and FOXO1 was poorly expressed in placental tissues of PE patients. Furthermore, H19 acts as a competitive endogenous RNA against let-7b, and let-7b directly targeted FOXO1. Moreover, H19 could be transferred to trophoblast cells via MSCsecreted exosomes. MSC-derived exosomes overexpressing H19 decreased let-7b, increased FOXO1, and activated the protein kinase B (AKT) signaling pathway, thus increasing invasion and migration and inhibiting apoptosis of trophoblast cells. These results suggest that MSC-derived exosomes overexpressing H19 may be a novel direction for therapeutic strategies against PE.

Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19

“…Indeed, H19 can act not only as an intrinsic factor, but can also act on neighboring cells. For instance, the involvement of the exosomes-derived expression of H19 has been demonstrated in specific phenomena and pathologies such as trophoblast cell invasion, diabetic foot ulcers, and chronic cholestatic liver diseases, supporting our idea that exosomal H19 can extend its action to surrounding cells [96][97][98]. In cancer models, it has been demonstrated that H19 expression is upregulated in non-small cells lung cancer, particularly in gefitinib-resistant cells.…”

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

“…MSC-originated exosomes overexpressing H19 reduced let-7b and strengthened forkhead box protein O1 (FOXO1) expression to trigger the protein kinase B (AKT) pathway, thus enhancing trophoblast activities. 8 A report summarized the exo-miRNA of umbilical cord blood in healthy and PE pregnant females systematically and validated that miR-125a-5p dysregulation might influence HTR8/SVneo cell angiogenesis, which is an indicative of miR-125a-5p involvement throughout PE progression. 10 Placenta-connected serum exosomes could constrain expression of endothelial nitric oxide synthase during PE progression in endothelial cells, and this occurrence may be fairly caused by raised miR-155 expression in the exosomes.…”

“…The expression of miR-139-3p in rat placental tissues was significantly restored and the expression of PETN and MMP-2 was significantly reduced which causes disfavored uterine placental perfusion. 8 MiRNA were found to interact with mRNA and signaling pathways to regulate biological processes of PE. 22,23 Our study searched the function of hucMSCsecreted exosomal miR-139-5p as well as the downstream PTEN and ERK/MMP-2 pathway in trophoblasts.…”

“…6 Successful isolation of mesenchymal stem cells (MSC) from the placental decidua basalis tissue of human PE was reported by Yasser S. Basmaeil et al 7 Furthermore, the exosomes emitted by MSC encompass the curative capacity to hinder apoptosis and stimulate angiogenesis in the placenta. 8 Interestingly, around 60% of the circulating microRNAs (miRNA) is linked with exosomes, and the miRNA in exosomes are resilient to RNase management. 9 miRNA play an essential role in placental-related disorders by binding to the 3 0 -untranslated region of target mRNA, thus hindering the expression of target mRNA.…”

Exosomal Long Non-Coding RNA: Interaction Between Cancer Cells and Non-Cancer Cells

“…For example, Yu, S. et al performed extracellular vesicle long RNA-seq (including lncRNA) on plasma samples collected from 501 subjects, and developed 8 long RNAs for the detection of pancreatic cancer ( 49 ). In addition, there are also studies based on star lncRNAs such as HOTAIR and H19 to explore their roles with exosomes in TME ( 50 , 51 ). Nowadays, a series of exosome databases that collect various public exosome sequencing data are constructed.…”