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- Title
Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis.
- 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
- 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.
- Subjects
VESICLES (Cytology); INTERFERONS; MESENCHYMAL stem cells; HEPATIC fibrosis; LIVER regeneration
- Publication
NPJ Regenerative Medicine, 2021, Vol 6, Issue 1, p1
- ISSN
2057-3995
- Publication type
Article
- DOI
10.1038/s41536-021-00132-4