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Small extracellular vesicles from Interferon-γ pre-conditioned mesenchymal stromal cells effectively improve liver fibrosis
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Suguru Takeuchi1,
Atsunori Tsuchiya1,
Shuji Terai1 |
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1Niigata University, Division of Gastroenterology and Hepatology |
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| Background: Therapeutic mechanism of mesenchymal stromal cells (MSCs) for cirrhosis is not fully established. Here, we show the therapeutic effect of small extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs) for cirrhosis. Methods: The effect of γ-sEVs for macrophage polarization, motility and phagocytosis ability, the proteome analysis of γ-sEVs, the effect of γ-sEVs agianst hepatic stellate cells (HSCs) activation, and the therapeutic effects of MSCs and sEVs with or without IFN-γ stimulation in cirrhosis mouse model using intravital imaging technique and single-cell transcriptome analysis were evaluated. Results: γ-sEVs can effectively induce anti-inflammatory macrophages in vitro and can enhance the motility and phagocytic ability. Proteome analysis of MSC derived sEVs could revealed the attractive proteins including annexin-A1 etc. after IFN-γ stimulation. However, γ-sEVs do not prevent the activation of HSCs cells in vitro suggesting that γ-sEVs do not have the direct inhibition of HSC activation. Furthermore, γ-sEVs could improve the inflammation and fibrosis in cirrhosis mouse at dose dependent manner with collecting the extrahepatic macrophages into the damaged area. Single cell transcriptome analysis revealed the wide range of effects such as induction of anti-inflammatory macrophages and regulatory T cell were observed after γ-sEVs administration. Conclusions: Our results that induction of γ-sEVs by pre-conditioning resulted in efficient cirrhosis tissue repair showed new therapeutic insight. |
Index Term 1: Cirrhosis
Index Term 2: Extracellular vesicle
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