Takeuchi Suguru, Tsuchiya Atsunori, Iwasawa Takahiro, Nojiri Shunsuke, Watanabe Takayuki, Ogawa Masahiro, Yoshida Tomoaki, Fujiki Katsunori, Koui Yuta, Kido Taketomo, Yoshioka Yusuke, Fujita Mayu, Kikuta Junichi, Itoh Tohru, Takamura Masaaki, Shirahige Katsuhiko, Ishii Masaru, Ochiya Takahiro, Miyajima Atsushi, Terai Shuji
Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1, Yayoi-Cho, Bunkyo-ku, Tokyo, 113-0032, Japan.
NPJ Regen Med. 2021 Mar 30;6(1):19. doi: 10.1038/s41536-021-00132-4.
Mesenchymal stromal cells (MSCs) are used for ameliorating liver fibrosis and aiding liver regeneration after cirrhosis; Here, we analyzed the therapeutic potential of small extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs). γ-sEVs effectively induced anti-inflammatory macrophages with high motility and phagocytic abilities in vitro, while not preventing hepatic stellate cell (HSC; the major source of collagen fiber) activation in vitro. The proteome analysis of MSC-derived sEVs revealed anti-inflammatory macrophage inducible proteins (e.g., annexin-A1, lactotransferrin, and aminopeptidase N) upon IFN-γ stimulation. Furthermore, by enabling CXCR1+ macrophage accumulation in the damaged area, γ-sEVs ameliorated inflammation and fibrosis in the cirrhosis mouse model more effectively than sEVs. Single cell RNA-Seq analysis revealed diverse effects, such as induction of anti-inflammatory macrophages and regulatory T cells, in the cirrhotic liver after γ-sEV administration. Overall, IFN-γ pre-conditioning altered sEVs resulted in efficient tissue repair indicating a new therapeutic strategy.
间充质基质细胞（MSCs）被用于改善肝纤维化并辅助肝硬化后的肝脏再生；在此，我们分析了源自经干扰素-γ（IFN-γ）预处理的间充质基质细胞的小细胞外囊泡（sEVs，即γ-sEVs）的治疗潜力。γ-sEVs在体外有效诱导出具有高迁移率和吞噬能力的抗炎性巨噬细胞，而在体外并不阻止肝星状细胞（HSC；胶原纤维的主要来源）的激活。对源自间充质基质细胞的sEVs进行蛋白质组分析，揭示了在IFN-γ刺激后出现的抗炎性巨噬细胞诱导蛋白（例如膜联蛋白-A1、乳铁传递蛋白和氨肽酶N）。此外，通过使CXCR1+巨噬细胞在受损区域积聚，γ-sEVs比sEVs更有效地改善了肝硬化小鼠模型中的炎症和纤维化。单细胞RNA测序分析揭示了在给予γ-sEVs后，肝硬化肝脏中出现了多种效应，如诱导抗炎性巨噬细胞和调节性T细胞。总体而言，IFN-γ预处理改变后的sEVs导致了有效的组织修复，表明这是一种新的治疗策略。
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