TY - JOUR
T1 - Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice
AU - Haga, Hiroaki
AU - Yan, Irene K.
AU - Takahashi, Kenji
AU - Matsuda, Akiko
AU - Patel, Tushar
N1 - Funding Information:
This work was supported in part by the Grants R01 DK069370 and UH2 TR000884 from the Office of the Director, National Institutes of Health and National Center for Advancing Translational Sciences (NCATS), and the Mayo Center for Regenerative Medicine.
Publisher Copyright:
© AlphaMed Press and 2017 The Authors.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cytokines
KW - Extracellular vesicles
KW - Fulminant hepatic failure
KW - Tumor necrosis factor
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U2 - 10.1002/sctm.16-0226
DO - 10.1002/sctm.16-0226
M3 - Article
C2 - 28213967
AN - SCOPUS:85017544552
SN - 2157-6564
VL - 6
SP - 1262
EP - 1272
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 4
ER -