Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis

Suguru Takeuchi; Atsunori Tsuchiya; Takahiro Iwasawa; Shunsuke Nojiri; Takayuki Watanabe; Masahiro Ogawa; Tomoaki Yoshida; Katsunori Fujiki; Yuta Koui; Taketomo Kido; Yusuke Yoshioka; Mayu Fujita; Junichi Kikuta; Tohru Itoh; Masaaki Takamura; Katsuhiko Shirahige; Masaru Ishii; Takahiro Ochiya; Atsushi Miyajima; Shuji Terai

doi:10.1038/s41536-021-00132-4

Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis

NPJ Regen Med. 2021 Mar 30;6(1):19. doi: 10.1038/s41536-021-00132-4.

Authors

Suguru Takeuchi¹, Atsunori Tsuchiya², Takahiro Iwasawa¹, Shunsuke Nojiri¹, Takayuki Watanabe¹, Masahiro Ogawa¹, Tomoaki Yoshida¹, Katsunori Fujiki³, Yuta Koui⁴, Taketomo Kido⁴, Yusuke Yoshioka⁵, Mayu Fujita⁶, Junichi Kikuta⁶, Tohru Itoh⁴, Masaaki Takamura¹, Katsuhiko Shirahige³, Masaru Ishii⁶, Takahiro Ochiya⁵, Atsushi Miyajima⁴, Shuji Terai⁷

Affiliations

¹ Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
² Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. atsunori@med.niigata-u.ac.jp.
³ 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.
⁴ Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.
⁵ Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
⁶ Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
⁷ Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. terais@med.niigata-u.ac.jp.

Abstract

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 CX₃CR1+ 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.

Abstract

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