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大学・研究所にある論文を検索できる 「TNF-a/IFN-a共刺激した歯肉幹細胞由来細胞外小胞は内包されるCD73/CD5Lを介して抗炎症性M2マクロファージの分化を誘導する」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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TNF-a/IFN-a共刺激した歯肉幹細胞由来細胞外小胞は内包されるCD73/CD5Lを介して抗炎症性M2マクロファージの分化を誘導する

渡邊, ゆかり WATANABE, Yukari ワタナベ, ユカリ 九州大学

2022.12.31

概要

近年、間葉系幹細胞(MSC)はその多分化能により再生目的組織の機能を代替するだけでなく、障害を受けた組織の再生を分泌物質により強力にサポートすることで治療効果を発揮するとした概念が提唱され、その活性中心を担う分泌物として細胞外小胞(EVs)が注目されている。歯肉幹細胞(GMSCs)は採取が容易なうえ、EVsの分泌能力が多い特徴を有する。先行研究において、GMSCs由来EVsによる抗炎症性M2型マクロファージの誘導効果と同時に、GMSCsへのTNF-a刺激によるEVs含有CD73を介した増強作用を報告した(Nakaoetal., Acta Biomater. 2021)。このような炎症刺激によるネガティブフィードバック機構は、MSCの治療効果を改善するための戦略として報告されつつあるが、詳細な分子基盤は不明点が多い。さらに、複数のサイトカインによる併用効果の報告は少ないうえ、IFN-gより強力な1型インターフェロンであるIFN-a刺激の報告はなかった。本研究ではTNF-aおよびIFN-aで前処理したGMSC由来EVsのM2マクロファージに対する誘導に対する相乗効果と、その分子機構解明のための検証を行った。

GMSCsへのTNF-a/IFN-a共刺激により、CD73mRNA発現およびGMSCs由来EVsのCD73蛋白発現が有意に亢進した。GMSCsにおけるTNF-a/IFN-a共刺激によるCD73発現誘導は、mTORの活性化によるHIF-1aの発現誘導を伴う核移行を介して制御される可能性が示唆された。TNF-a/IFN-a共刺激GMSC由来EVsは、無刺激およびTNF-a/IFN-a単独刺激GMSC由来EVsと比較し、炎症性M1マクロファージを抗炎症M2マクロファージへの分化転換能が促進されることが確認された。さらに、GMSCへのTNF-a/IFN-a共刺激により、転写因子ID3、LXRを介したCD5LmRNAの発現亢進が確認されたが、そのほとんどが直接分泌されることなくEVs含有蛋白としてGMSCsより放出されることが示唆された。リコンビナントCD5L単独刺激によるM2マクロファージ分化誘導能とともに、CD5LをノックダウンしたGMSCへのTNF-a/IFN-a共刺激EVsでは、M2マクロファージの誘導能が阻害された。

以上より、TNF-a/IFN-a共刺激GMSCs由来EVsは含有CD73/CD5Lの促進を介して相乗的にM2マクロファージ誘導能が増強されることが明らかとなった。

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