Extracellular vesicles derived from GMSCs stimulated with TNF-α and IFN-α promote M2 macrophage polarization via enhanced CD73 and CD5L expression

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  • Watanabe, Yukari
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Fukuda, Takao
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Hayashi, Chikako
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Nakao, Yuki
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Toyoda, Masaaki
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Kawakami, Kentaro
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Shinjo, Takanori
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Iwashita, Misaki
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Yamato, Hiroaki
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Yotsumoto, Karen
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Taketomi, Takaharu
    Department of Dental and Oral Surgery, St. Mary’s Hospital
  • Uchiumi, Takeshi
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University
  • Sanui, Terukazu
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University
  • Nishimura, Fusanori
    Division of Oral Rehabilitation, Department of Periodontology, Faculty of Dental Science, Kyushu University

Description

Immunoregulatory properties of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising. Gingival tissue-derived MSCs (GMSCs) have unique immunoregulatory capacity and secrete large amounts of EVs. Recent findings suggest that priming MSCs with inflammatory stimuli is an effective strategy for cell-free therapy. However, the precise mechanism by which the contents of EVs are customized has not been fully elucidated. Here, we show that EVs derived from GMSCs primed with a combination of two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), synergistically promote anti-inflammatory M2 macrophage polarization by increasing the expression of cluster of differentiation 73 (CD73) and CD5 molecule-like (CD5L). Expression of CD73 by TNF-α/IFN-α stimulation was transcriptionally upregulated by the activation of mammalian target of rapamycin signaling and nuclear translocation of hypoxia-inducible factor 1α in GMSCs. TNF-α/IFN-α treatment also significantly increased the expression of CD5L mRNA via the transcription factor DNA-binding protein inhibitor ID3 and liver X receptor. Interestingly, exosomal CD5L is a prerequisite for the synergistic effect of EVs-mediated M2 macrophage polarization. These results indicate that combined pre-licensing with TNF-α and IFN-α in GMSCs is ideal for enhancing the anti-inflammatory function of EVs, which contributes to the establishment of a therapeutic tool.

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