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

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

doi:10.1038/s41536-021-00132-4

Cited by 61 publications

(73 citation statements)

References 57 publications

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“…Same-pathway SMAD was described to be modified by the exosomes secreted by MSCs in an injured endometrium repaired by fibrosis [ 136 ]. Takeuchi et al analyzed the proteome of EVs derived from MSCs, describing an increase in anti-inflammatory macrophage-inducible proteins (e.g., annexin-A1, lactotransferrin and aminopeptidase N), which triggered liver regeneration after fibrosis and cirrhosis; they pre-conditioned the EVs with an IFN-γ treatment, and the pre-conditioning-altered sEVs resulted in efficient tissue repair, indicating a new therapeutic strategy to treat fibrosis in a mouse model of cirrhosis [ 137 ].…”

Section: Mscs As a Treatment Of Several Typical Pathologies Regarding Wound Healingmentioning

confidence: 99%

The Role of MSC in Wound Healing, Scarring and Regeneration

Guillamat-Prats

2021

Cells

217

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Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis.

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Section: Mscs As a Treatment Of Several Typical Pathologies Regarding Wound Healingmentioning

confidence: 99%

The Role of MSC in Wound Healing, Scarring and Regeneration

Guillamat-Prats

2021

Cells

217

123

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“…Our results after injecting MSCs were consistent with those of a previous study [ 6 ]. Xenogenic human MSCs are useful for their effect on murine liver injury models [ 7 , 8 ]. Watanabe et al.…”

Section: Discussionmentioning

confidence: 99%

“…This is consistent with our finding that NK cells increased in the liver. As IFN-γ has been reported to kill activated hepatic stellate cells [ 26 ] and strengthen the anti-inflammatory effects of MSCs [ 8 ], it is possible that IFN-γ and other factors induced by JTT also enhance the therapeutic effects of MSCs. Induction of Treg cells by JTT has not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, their anti-oxidative effect can reduce hepatocyte damage and inactivate immune cells, thereby suppressing HSC activation and fibrogenesis. In addition, MSCs can activate anti-inflammatory macrophages that lead to fibrolysis [ [6] , [7] , [8] ]. However, to enhance the therapeutic effect of MSCs, they are administered in combination with conventionally used drugs.…”

Section: Introductionmentioning

confidence: 99%

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Combination therapy of Juzentaihoto and mesenchymal stem cells attenuates liver damage and regresses fibrosis in mice

Iwasawa

Nojiri

Tsuchiya

et al. 2021

Regenerative Therapy

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Background Liver cirrhosis is an end-stage multiple liver disease. Mesenchymal stem cells (MSCs) are an attractive cell source for reducing liver damage and regressing fibrosis; additional therapies accompanying MSCs can potentially enhance their therapeutic effects. Kampo medicines exhibit anti-inflammatory and anti-oxidative effects. Here, we investigated the therapeutic effect of MSCs combined with the Kampo medicine Juzentaihoto (JTT) as a combination therapy in a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. Methods C57BL/6 mice were administered JTT (orally) and/or MSCs (one time, intravenously). The levels of liver proteins were measured in the sera. Sirius Red staining and hydroxyproline quantitation of hepatic tissues and immune cells were conducted, and their associated properties were evaluated. Liver metabolomics of liver tissues was performed. Results JTT monotherapy attenuated liver damage and increased serum albumin level, but it did not effectively induce fibrolysis. JTT rapidly reduced liver damage, in a dose-dependent manner, after a single-dose CCl4 administration. Furthermore, JTT-MSC combination therapy attenuated liver damage, improved liver function, and regressed liver fibrosis. The combination increased the CD4+/CD8+ ratio. JTT had stronger effects on NK and regulatory T cell induction, whereas MSCs more strongly induced anti-inflammatory macrophages. The combination therapy further induced anti-inflammatory macrophages. JTT normalized lipid mediators, and tricarboxylic acid cycle- and urea cycle-related mediators effectively. Conclusions The addition of JTT enhanced the therapeutic effects of MSCs; this combination could be a potential treatment option for cirrhosis.

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“…The PEG hydrogels can prolong the bioavailability of MSC-EVs in targeted livers, thus enhancing the anti-fibrosis characteristics thereof [ 58 ]. Relative to MSC-EVs, MSC-EVs preconditioned with IFN-γ better alleviate the inflammation and fibrosis of the murine model with liver cirrhosis [ 59 ].…”

Section: Msc-evs and Fibrotic Diseasesmentioning

confidence: 99%

Mesenchymal stem cell-derived extracellular vesicles in therapy against fibrotic diseases

Huang

Yang

2021

Stem Cell Res Ther

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Fibrosis is likely to occur in many tissues and organs to induce cicatrisation and dysfunction. The therapeutic regimens for delaying and even reversing fibrosis are quite limited at present. In nearly a decade, mesenchymal stem cells (MSCs) have been widely acknowledged as useful in treating fibrotic diseases in preclinical and clinical trials. Further preclinical studies indicated that the effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are probably superior to that of MSCs. At present, MSC-EVs have attracted much attention in treating fibrosis of lung, liver, kidney, skin, and heart. By contrast, a significant knowledge-gap remains in treating fibrosis of other tissues and organs (including uterus, gastrointestinal tract, and peritoneum) with the aid of MSC-EVs. This review summarises the preclinical research status of MSC-EVs in treating fibrotic diseases and proposes solutions to existing problems, which contribute to further clinical research on the treatment of fibrotic diseases with MSC-EVs in the future.

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

Cited by 61 publications

References 57 publications

The Role of MSC in Wound Healing, Scarring and Regeneration

The Role of MSC in Wound Healing, Scarring and Regeneration

Combination therapy of Juzentaihoto and mesenchymal stem cells attenuates liver damage and regresses fibrosis in mice

Mesenchymal stem cell-derived extracellular vesicles in therapy against fibrotic diseases

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