title: Extracellular Vesicles from Bone Marrow-Derived Mesenchymal Stem Cells Improve Survival from Lethal Hepatic Failure in Mice.
abstract: 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.
authors.affiliation: Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.|Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.|Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Yan
authors.affiliation: Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.|Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.|Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.|Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology*; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000502:physiology*; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000628:therapy*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
keywords: Apoptosis; Cytokines; Extracellular vesicles; Fulminant hepatic failure; Tumor necrosis factor