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Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.

ABSTRACT: microRNA-126 (miR-126), an endothelial-specific miRNA, is associated with vascular homeostasis and angiogenesis. However, the efficiency of miR-126-based treatment is partially compromised due to the low efficiency of miRNA delivery in vivo. Lately, exosomes have emerged as a natural tool for therapeutic molecule delivery. Herein, we investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) can be utilized to deliver miR-126 to promote angiogenesis. Exosomes were isolated from BMMSCs overexpressed with miR-126 (Exo-miR-126) by ultracentrifugation. In vitro study, Exo-miR-126 treatment promoted the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, the gene/protein expression of angiogenesis-related vascular endothelial growth factor (VEGF) and angiotensin-1 (Ang-1) were up-regulated after incubation with Exo-miR-126. Additionally, the expression level of phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) showed an inverse correlation with miR-126 in HUVECs. Particularly, the Exo-miR-126 treatment contributed to enhanced angiogenesis of HUVECs by targeting PIK3R2 to activate the PI3K/Akt signalling pathway. Similarly, Exo-miR-126 administration profoundly increased the number of newly formed capillaries in wound sites and accelerated the wound healing in vivo. The results demonstrate that exosomes derived from BMMSCs combined with miR-126 may be a promising strategy to promote angiogenesis.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7882955 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.

Zhang Lei L Ouyang Pengrong P He Gaole G Wang Xiaowei X Song Defu D Yang Yijun Y He Xijing X

Journal of cellular and molecular medicine 20201221 4

microRNA-126 (miR-126), an endothelial-specific miRNA, is associated with vascular homeostasis and angiogenesis. However, the efficiency of miR-126-based treatment is partially compromised due to the low efficiency of miRNA delivery in vivo. Lately, exosomes have emerged as a natural tool for therapeutic molecule delivery. Herein, we investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) can be utilized to deliver miR-126 to promote angiogenesis. Exosomes were iso ...[more]

PMID: 33350092

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Project description:BackgroundThe abnormal expression of long noncoding RNA (LncRNA) HOTAIR has been associated with synovial angiogenesis in rheumatoid arthritis (RA). The aim of this study is to investigate whether LncRNA HOTAIR plays a role in synovial angiogenesis in RA by regulating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway through the miR-126-3p/PIK3R2 axis.MethodsIn this study, we conducted in vitro experiments by designing overexpression plasmids and small interfering RNAs targeting LncRNA HOTAIR and then transfected them into rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). We then co-cultured the RA-FLS with human umbilical vein endothelial cells (HUVEC) to establish a RA-FLS-induced HUVEC model. We investigated the effects of LncRNA HOTAIR on the proliferation, migration, lumen forming ability of HUVEC, as well as the expression of synovial endothelial cell markers, angiogenic factors, and the PI3K/AKT pathway. To validate the interactions between LncRNA HOTAIR, miR-126-3p, and PIK3R2, we used bioinformatics and luciferase reporter experiments. We also employed real-time fluorescence quantitative, Western blotanalysis, and immunofluorescence techniques to analyze the target genes and proteins.ResultsThe expression of LncRNA HOTAIR was upregulated in HUVEC induced by RA-FLS. The overexpression of LncRNA HOTAIR significantly increased the expression of vascular endothelial growth factor, basic fibroblast growth factor, CD34, and CD105 in HUVEC, promoting their proliferation, migration, and lumen formation. At the same time, the overexpression of LncRNA HOTAIR inhibited the expression of miR-126-3p, promoted the expression of PIK3R2, activated the PI3K/AKT pathway, and promoted the expression of PI3K, AKT and phosphorylated-AKT, while the silence of LncRNA HOTAIR reversed these expressions. Bioinformatics and double luciferase reporter gene experiments confirmed the targeting relationship among LncRNA HOTAIR, miR-126-3p, and PIK3R2. Finally, the rescue experiments showed that PI3K agonists could reverse the inhibitory effect of silent LncRNA HOTAIR on HUVEC.ConclusionLncRNA HOTAIR has the potential to activate the PI3K/AKT pathway, likely through the regulatory axis involving miR-126-3p/PIK3R2, consequently contributing to synovial angiogenesis in RA.

Dataset Information

Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.

Publications

Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.

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