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Mesenchymal stem cells-derived extracellular vesicles containing miR-378a-3p inhibit the occurrence of inflammatory bowel disease by targeting GATA2.

ABSTRACT: This study sought to determine whether mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) carrying microRNA-378a-3p (miR-378a-3p) could affect the pathogenesis of inflammatory bowel disease (IBD) by regulating the GATA-binding protein 2 (GATA2)/aquaporin-4 (AQP4)/peroxisome proliferator-activated receptor α (PPAR-α) axis. Initially, colon mucosa biopsy tissues were harvested from healthy controls and patients with IBD for qRT-PCR and immunohistochemistry analysis. EVs harvested from MSCs and lipopolysaccharide (LPS) were used to stimulate the M064 cells to establish an in vitro inflammation cell model. Besides, 2,4,6-trinitrobenzene sulfonic acid intracolon administration was performed to establish in vivo IBD mouse models. After loss- and gain-of-function assays, the regulatory role of MSCs-derived EVs loaded with manipulated miR-378a-3p in IBD in relation to GATA2/AQP4/PPAR-α were explored. Upregulation of GATA2 was identified in the colon tissue of IBD patients. GATA2, which was a target gene of miR-378a-3p, transcriptionally upregulated AQP4. After silencing of GATA2, LPS-induced apoptosis of M064 cells was reduced by the downregulation of AQP4. Decreased AQP4 contributed to PPAR-α pathway inactivation and weakened the LPS-induced apoptosis of M064 cells. MSCs-EVs delivering miR-378a-3p suppressed the GATA2/AQP4/PPAR-α pathway, which reduced LPS-induced apoptosis of M064 cells and the occurrence of IBD in mice. Altogether, the current study illustrated that MSCs-EVs transfer miR-378a-3p to reduce the GATA2 expression, which downregulates AQP4 to block the PPAR-α signalling pathway, thus suppressing the occurrence of IBD.

SUBMITTER: Li P

PROVIDER: S-EPMC9170824 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells-derived extracellular vesicles containing miR-378a-3p inhibit the occurrence of inflammatory bowel disease by targeting GATA2.

Li Ping P Zhang Hai-Yan HY Gao Jian-Zhen JZ Du Wen-Qiang WQ Tang Dong D Wang Wei W Wang Liu-Hua LH

Journal of cellular and molecular medicine 20220517 11

This study sought to determine whether mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) carrying microRNA-378a-3p (miR-378a-3p) could affect the pathogenesis of inflammatory bowel disease (IBD) by regulating the GATA-binding protein 2 (GATA2)/aquaporin-4 (AQP4)/peroxisome proliferator-activated receptor α (PPAR-α) axis. Initially, colon mucosa biopsy tissues were harvested from healthy controls and patients with IBD for qRT-PCR and immunohistochemistry analysis. EVs harvested fro ...[more]

PMID: 35582765

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Project description:BackgroundExtracellular vesicles (EVs) are a group of nanoscale cell-derived membranous structures secreted by all cell types, containing molecular cargoes involved in intercellular communication. EVs can be used to mimic "nature's delivery system" to transport nucleic acids, peptides, lipids, and metabolites to target recipient cells. EVs offer a range of advantages over traditional synthetic carriers, thus paving the way for innovative drug delivery approaches that can be used in different diseases, including cancer. Here, by using breast cancer (BC) cells treated with the multi-kinase inhibitor sorafenib, we generated EVs enriched in specific non-coding RNAs (miR-23b-3p, miR-126-3p, and the long ncRNA GAS5) and investigated their potential impact on the aggressive properties of the BC in vitro and in vivo using zebrafish.MethodsEVs were collected from 4 different BC cell lines (HCC1937, MDA-MB-231, MCF-7, and MDA-MB-453) and characterized by western blotting, transmission electron microscopy and nanoparticle tracking analysis. Levels of encapsulated miR-23b-3p, miR-126-3p, and GAS5 were quantified by ddPCR. The role of the EVs as carriers of ncRNAs in vivo was established by injecting MDA-MB-231 and MDA-MB-453 cells into zebrafish embryos followed by EV-based treatment of the xenografts with EVs rich in miR-23b-3p, miR-126-3p and GAS5.ResultsddPCR analysis revealed elevated levels of miR-23b-3p, miR-126-3p, and GAS5, encapsulated in the EVs released by the aforementioned cell lines, following sorafenib treatment. The use of EVs as carriers of these specific ncRNAs in the treatment of BC cells resulted in a significant increase in the expression levels of the three ncRNAs along with the inhibition of cellular proliferation in vitro. In vivo experiments demonstrated a remarkable reduction of xenograft tumor area, suppression of angiogenesis, and decreased number of micrometastasis in the tails after administration of EVs enriched with these ncRNAs.ConclusionsOur study demonstrated that sorafenib-induced EVs, enriched with specific tumor-suppressor ncRNAs, can effectively inhibit the aggressive BC characteristics in vitro and in vivo. Our findings indicate an alternative way to enrich EVs with specific tumor-suppressor ncRNAs by treating the cells with an anticancer drug and support the development of new potential experimental molecular approaches to target the aggressive properties of cancer cells.

Dataset Information

Mesenchymal stem cells-derived extracellular vesicles containing miR-378a-3p inhibit the occurrence of inflammatory bowel disease by targeting GATA2.

Publications

Mesenchymal stem cells-derived extracellular vesicles containing miR-378a-3p inhibit the occurrence of inflammatory bowel disease by targeting GATA2.

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