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

• Published in: npj Regenerative medicine Vol. 6; no. 1; p. 19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 30.03.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Extracellular vesicles; Liver; Liver cirrhosis
• ISSN: 2057-3995; 2057-3995
• 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 CX CR1+ 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.