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MicroRNA-301a inhibition enhances the immunomodulatory functions of adipose-derived mesenchymal stem cells by induction of macrophage M2 polarization.

ABSTRACT: MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a significant role in biological processes in various cell types, including mesenchymal stem cells (MSCs). However, how miRNAs regulate the immunomodulatory functions of adipose-derived MSCs (AD-MSCs) remains unknown. Here, we showed that modulation of miR-301a in AD-MSCs altered macrophage polarization. Bone marrow (BM)-derived macrophages were stimulated with LPS (1??g/ml) and co-cultured with miRNA transfected AD-MSCs for 24?h. The expression of M1 and M2 markers in macrophages was analyzed. Inhibition of miR-301a induced M2 macrophage with arginase-1, CD163, CD206, and IL-10 upregulation. Additionally, toll-like receptor (TLR)-4 mRNA expression in macrophages was downregulated in co-cultures with AD-MSCs transfected with a miR-301a inhibitor. Nitric oxide (NO) in the supernatant of AD-MSC/macrophage co-culture was also suppressed by inhibition of miR-301a in AD-MSCs. We further found that suppression of miR-301a in AD-MSCs increased prostaglandin E2 (PGE2) concentration in the conditioned medium of the co-culture. Taken together, the results of our study indicate that miR-301a can modulate the immunoregulatory functions of AD-MSCs that favor the applicability as a potential immunotherapeutic agent.

SUBMITTER: Hsu LW

PROVIDER: S-EPMC7607751 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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MicroRNA-301a inhibition enhances the immunomodulatory functions of adipose-derived mesenchymal stem cells by induction of macrophage M2 polarization.

Hsu Li-Wen LW Huang Kuang-Tzu KT Nakano Toshiaki T Chiu King-Wah KW Chen Kuang-Den KD Goto Shigeru S Chen Chao-Long CL

International journal of immunopathology and pharmacology 20200101

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a significant role in biological processes in various cell types, including mesenchymal stem cells (MSCs). However, how miRNAs regulate the immunomodulatory functions of adipose-derived MSCs (AD-MSCs) remains unknown. Here, we showed that modulation of miR-301a in AD-MSCs altered macrophage polarization. Bone marrow (BM)-derived macrophages were stimulated with LPS (1 μg/ml) and co-cultured with miRNA transfected AD-MSCs for 24 h. ...[more]

PMID: 33121303

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Project description:BackgroundSolid tumors promote tumor malignancy through interaction with the tumor microenvironment, resulting in difficulties in tumor treatment. Therefore, it is necessary to understand the communication between cells in the tumor and the surrounding microenvironment. Our previous study revealed the cancer malignancy mechanism of Bcl-w overexpressed in solid tumors, but no study was conducted on its relationship with immune cells in the tumor microenvironment. In this study, we sought to discover key factors in exosomes secreted from tumors overexpressing Bcl-w and analyze the interaction with the surrounding tumor microenvironment to identify the causes of tumor malignancy.MethodsTo analyze factors affecting the tumor microenvironment, a miRNA array was performed using exosomes derived from cancer cells overexpressing Bcl-w. The discovered miRNA, miR-6794-5p, was overexpressed and the tumorigenicity mechanism was confirmed using qRT-PCR, Western blot, invasion, wound healing, and sphere formation ability analysis. In addition, luciferase activity and Ago2-RNA immunoprecipitation assays were used to study the mechanism between miR-6794-5p and its target gene SOCS1. To confirm the interaction between macrophages and tumor-derived miR-6794-5p, co-culture was performed using conditioned media. Additionally, immunohistochemical (IHC) staining and flow cytometry were performed to analyze macrophages in the tumor tissues of experimental animals.ResultsMiR-6794-5p, which is highly expressed in exosomes secreted from Bcl-w-overexpressing cells, was selected, and it was shown that the overexpression of miR-6794-5p increased migratory ability, invasiveness, and stemness maintenance by suppressing the expression of the tumor suppressor SOCS1. Additionally, tumor-derived miR-6794-5p was delivered to THP-1-derived macrophages and induced M2 polarization by activating the JAK1/STAT3 pathway. Moreover, IL-10 secreted from M2 macrophages increased tumorigenicity by creating an immunosuppressive environment. The in vitro results were reconfirmed by confirming an increase in M2 macrophages and a decrease in M1 macrophages and CD8+ T cells when overexpressing miR-6794-5p in an animal model.ConclusionsIn this study, we identified changes in the tumor microenvironment caused by miR-6794-5p. Our study indicates that tumor-derived miR-6794-5p promotes tumor aggressiveness by inducing an immunosuppressive environment through interaction with macrophage.

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Dataset Information

MicroRNA-301a inhibition enhances the immunomodulatory functions of adipose-derived mesenchymal stem cells by induction of macrophage M2 polarization.

Publications

MicroRNA-301a inhibition enhances the immunomodulatory functions of adipose-derived mesenchymal stem cells by induction of macrophage M2 polarization.

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