Extracellular Vesicles from Bone Marrow‐Derived Mesenchymal Stem Cells Improve Survival from Lethal Hepatic Failure in Mice

• Published in: Stem cells translational medicine Vol. 6; no. 4; pp. 1262 - 1272
• Main Authors: Haga, Hiroaki, Yan, Irene K., Takahashi, Kenji, Matsuda, Akiko, Patel, Tushar
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-04-2017; John Wiley and Sons Inc
• Subjects: Animal models; Apoptosis; Bone marrow; Cell growth; Cell interactions; Cell signaling; Chemokines; Cryopreservation; Cytokines; D-Galactosamine; Data analysis; Extracellular vesicles; Fulminant hepatic failure; Liver; Mesenchymal stem cells; Mesenchyme; Mortality; Paracrine signalling; siRNA; Stem cell transplantation; Stem cells; Tissue Engineering and Regenerative Medicine; Translational s and Reviews; Transmission electron microscopy; Tumor necrosis factor; Tumor necrosis factor-TNF; United States > US; Grand Island New York; Extracellular vesicles; Cytokines; Tumor necrosis factor; Fulminant hepatic failure; Apoptosis
• ISSN: 2157-6564; 2157-6580
• DOI: 10.1002/sctm.16-0226

Stem cell‐based therapies have potential for treatment of liver injury by contributing to regenerative responses, through functional tissue replacement or paracrine effects. The release of extracellular vesicles (EV) from cells has been implicated in intercellular communication, and may contribute to beneficial paracrine effects of stem cell‐based therapies. Therapeutic effects of bone‐marrow derived mesenchymal stem cells (MSC) and vesicles released by these cells were examined in a lethal murine model of hepatic failure induced by d‐galactosamine/tumor necrosis factor‐α (TNF‐α). Systemically administered EV derived from MSC accumulated within the injured liver following systemic administration, reduced hepatic injury, and modulated cytokine expression. Moreover, survival was dramatically increased by EV derived from either murine or human MSC. Similar results were observed with the use of cryopreserved mMSC‐EV after 3 months. Y‐RNA‐1 was identified as a highly enriched noncoding RNA within hMSC‐EV compared to cells of origin. Moreover, siRNA mediated knockdown of Y‐RNA‐1 reduced the protective effects of MSC‐EV on TNF‐α/ActD‐mediated hepatocyte apoptosis in vitro. These data support a critical role for MSC‐derived EV in mediating reparative responses following hepatic injury, and provide compelling evidence to support the therapeutic use of MSC‐derived EV in fulminant hepatic failure. Stem Cells Translational Medicine 2017;6:1262–1272