{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:12:45Z","timestamp":1790626365126,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T00:00:00Z","timestamp":1495756800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T00:00:00Z","timestamp":1495756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver Transpl"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>Hepatic ischemia\/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC\u2010EV) on tissue injury. The effects of systemically administered mouse bone marrow\u2013derived MSC\u2010EV were evaluated in an experimental murine model of hepatic IRI induced by cross\u2010clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC\u2010EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3\u2013positive and apoptotic cells, and reduced serum aminotransferase levels. MSC\u2010EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains\u2010containing protein 12, and the chemokine (C\u2010X\u2010C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC\u2010EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow\u2013derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.<jats:italic toggle=\"yes\">Liver Transplantation 23 791\u2013803 2017 AASLD<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/lt.24770","type":"journal-article","created":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T18:36:00Z","timestamp":1492108560000},"page":"791-803","source":"Crossref","is-referenced-by-count":115,"title":["Extracellular vesicles from bone marrow\u2013derived mesenchymal stem cells protect against murine hepatic ischemia\/reperfusion injury"],"prefix":"10.1097","volume":"23","author":[{"given":"Hiroaki","family":"Haga","sequence":"first","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene K.","family":"Yan","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansi","family":"Parasramka","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Shukla","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David D.","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tushar","family":"Patel","sequence":"additional","affiliation":[{"name":"Departments of Transplantation and Cancer Biology,Mayo Clinic,Jacksonville,Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,5,26]]},"reference":[{"key":"lt24770-bib-0001-20240115","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1053\/jhep.2000.9323","article-title":"Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia\/reperfusion injury","volume":"32","year":"2000","journal-title":"Hepatology"},{"key":"lt24770-bib-0002-20240115","first-page":"454","article-title":"Hepatic resection with ischemia of the liver exceeding one hour","volume":"178","year":"1994","journal-title":"J Am Coll Surg"},{"key":"lt24770-bib-0003-20240115","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1146\/annurev.pharmtox.37.1.327","article-title":"Reperfusion injury after liver preservation for transplantation","volume":"37","year":"1997","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"lt24770-bib-0004-20240115","first-page":"509","article-title":"Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock","volume":"106","year":"1989","journal-title":"Surgery"},{"key":"lt24770-bib-0005-20240115","doi-asserted-by":"crossref","first-page":"e19195","DOI":"10.1371\/journal.pone.0019195","article-title":"Bone marrow\u2010derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model","volume":"6","year":"2011","journal-title":"PLoS One"},{"key":"lt24770-bib-0006-20240115","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.surg.2014.05.008","article-title":"Human adipose\u2010derived mesenchymal stem cells attenuate liver ischemia\u2010reperfusion injury and promote liver regeneration","volume":"156","year":"2014","journal-title":"Surgery"},{"key":"lt24770-bib-0007-20240115","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1097\/CCM.0b013e31823dae23","article-title":"Systemic administration of autologous adipose\u2010derived mesenchymal stem cells alleviates hepatic ischemia\u2010reperfusion injury in rats","volume":"40","year":"2012","journal-title":"Crit Care Med"},{"key":"lt24770-bib-0008-20240115","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.3892\/ijmm.2013.1340","article-title":"Allogeneic bone marrow\u2010derived mesenchymal stem cells attenuate hepatic ischemia\u2010reperfusion injury by suppressing oxidative stress and inhibiting apoptosis in rats","volume":"31","year":"2013","journal-title":"Int J Mol Med"},{"key":"lt24770-bib-0009-20240115","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.scr.2013.01.002","article-title":"Mesenchymal stem cell\u2010derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K\/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia\/reperfusion injury","volume":"10","year":"2013","journal-title":"Stem Cell Res"},{"key":"lt24770-bib-0010-20240115","first-page":"29","article-title":"Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model","volume":"7","year":"2008","journal-title":"Hepatobiliary Pancreat Dis Int"},{"key":"lt24770-bib-0011-20240115","first-page":"27","article-title":"Challenges in using stem cells for cardiac repair","volume":"2","year":"2010","journal-title":"Sci Transl Med"},{"key":"lt24770-bib-0012-20240115","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/hep.22236","article-title":"Mesenchymal stem cell\u2010derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo","volume":"47","year":"2008","journal-title":"Hepatology"},{"key":"lt24770-bib-0013-20240115","doi-asserted-by":"crossref","first-page":"e941","DOI":"10.1371\/journal.pone.0000941","article-title":"Mesenchymal stem cell\u2010derived molecules reverse fulminant hepatic failure","volume":"2","year":"2007","journal-title":"PLoS One"},{"key":"lt24770-bib-0014-20240115","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.jss.2012.04.070","article-title":"Bone marrow mesenchymal stem cells ameliorate hepatic ischemia\/reperfusion injuries via inactivation of the MEK\/ERK signaling pathway in rats","volume":"178","year":"2012","journal-title":"J Surg Res"},{"key":"lt24770-bib-0015-20240115","doi-asserted-by":"crossref","first-page":"e103355","DOI":"10.1371\/journal.pone.0103355","article-title":"The role of N\u2010acetyltransferase 8 in mesenchymal stem cell\u2010based therapy for liver ischemia\/reperfusion injury in rats","volume":"9","year":"2014","journal-title":"PLoS One"},{"key":"lt24770-bib-0016-20240115","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.scr.2009.12.003","article-title":"Exosome secreted by MSC reduces myocardial ischemia\/reperfusion injury","volume":"4","year":"2010","journal-title":"Stem Cell Res"},{"key":"lt24770-bib-0017-20240115","first-page":"3472","article-title":"Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton's Jelly mesenchymal stem cells after myocardial infarction","volume":"125","year":"2012","journal-title":"Chin Med J (Engl)"},{"key":"lt24770-bib-0018-20240115","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1089\/hum.2008.016","article-title":"Kallikrein\u2010modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation","volume":"19","year":"2008","journal-title":"Hum Gene Ther"},{"key":"lt24770-bib-0019-20240115","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1093\/ndt\/gfr015","article-title":"Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia\u2010reperfusion\u2010induced acute and chronic kidney injury","volume":"26","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"lt24770-bib-0020-20240115","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1681\/ASN.2008070798","article-title":"Mesenchymal stem cell\u2010derived microvesicles protect against acute tubular injury","volume":"20","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"lt24770-bib-0021-20240115","doi-asserted-by":"crossref","first-page":"e33115","DOI":"10.1371\/journal.pone.0033115","article-title":"Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury","volume":"7","year":"2012","journal-title":"PLoS One"},{"key":"lt24770-bib-0022-20240115","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1440-1797.2012.01589.x","article-title":"Bone marrow stem cells\u2010derived microvesicles protect against renal injury in the mouse remnant kidney model","volume":"17","year":"2012","journal-title":"Nephrology (Carlton)"},{"key":"lt24770-bib-0023-20240115","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: exosomes, microvesicles, and friends","volume":"200","year":"2013","journal-title":"J Cell Biol"},{"key":"lt24770-bib-0024-20240115","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/sctm.16-0226","article-title":"Extracellular vesicles from bone marrow\u2010derived mesenchymal stem cells improve survival from lethal hepatic failure in mice","volume":"6","year":"2017","journal-title":"Stem Cells Transl Med"},{"key":"lt24770-bib-0025-20240115","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/BF02618288","article-title":"Mouse liver cell culture. I. Hepatocyte isolation","volume":"17","year":"1981","journal-title":"In vitro"},{"key":"lt24770-bib-0026-20240115","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2008.09.029","article-title":"Mouse model of liver ischemia and reperfusion injury: method for studying reactive oxygen and nitrogen metabolites in vivo","volume":"46","year":"2009","journal-title":"Free Radic Biol Med"},{"key":"lt24770-bib-0027-20240115","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1046\/j.1440-1746.2003.03056.x","article-title":"Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection","volume":"18","year":"2003","journal-title":"J Gastroenterol Hepatol"},{"key":"lt24770-bib-0028-20240115","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.exphem.2010.04.007","article-title":"Bone marrow stem cells and liver regeneration","volume":"38","year":"2010","journal-title":"Exp Hematol"},{"key":"lt24770-bib-0029-20240115","doi-asserted-by":"crossref","first-page":"182","DOI":"10.2174\/157488810791268636","article-title":"Stem cells for hepatic regeneration: the role of adipose tissue derived mesenchymal stem cells","volume":"5","year":"2010","journal-title":"Curr Stem Cell Res Ther"},{"key":"lt24770-bib-0030-20240115","doi-asserted-by":"crossref","first-page":"11002","DOI":"10.1073\/pnas.0704421104","article-title":"Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury","volume":"104","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"lt24770-bib-0031-20240115","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1182\/blood-2005-04-1496","article-title":"Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T\u2010cell anergy","volume":"106","year":"2005","journal-title":"Blood"},{"key":"lt24770-bib-0032-20240115","doi-asserted-by":"crossref","first-page":"132","DOI":"10.12659\/AOT.892364","article-title":"Long\u2010term influence of bone marrow\u2010derived mesenchymal stem cells on liver ischemia\u2010reperfusion injury in a rat model","volume":"20","year":"2015","journal-title":"Ann Transplant"},{"key":"lt24770-bib-0033-20240115","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.jss.2012.04.070","article-title":"Bone marrow mesenchymal stem cells ameliorate hepatic ischemia\/reperfusion injuries via inactivation of the MEK\/ERK signaling pathway in rats","volume":"178","year":"2012","journal-title":"J Surg Res"},{"key":"lt24770-bib-0034-20240115","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jss.2012.02.014","article-title":"Adipose tissue\u2010derived mesenchymal stem cell transplantation promotes hepatic regeneration after hepatic ischemia\u2010reperfusion and subsequent hepatectomy in rats","volume":"178","year":"2012","journal-title":"J Surg Res"},{"key":"lt24770-bib-0035-20240115","first-page":"5761487","article-title":"Fate and effect of intravenously infused mesenchymal stem cells in a mouse model of hepatic ischemia reperfusion injury and resection","volume":"2016","year":"2016","journal-title":"Stem Cells Int"},{"key":"lt24770-bib-0036-20240115","first-page":"297","article-title":"Mesenchymal stem cells are short\u2010lived and do not migrate beyond the lungs after intravenous infusion","volume":"3","year":"2012","journal-title":"Front Immunol"},{"key":"lt24770-bib-0037-20240115","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.transproceed.2006.12.019","article-title":"Stem cell transplantation: the lung barrier","volume":"39","year":"2007","journal-title":"Transplant Proc"},{"key":"lt24770-bib-0038-20240115","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.mvr.2009.02.001","article-title":"Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy","volume":"77","year":"2009","journal-title":"Microvasc Res"},{"key":"lt24770-bib-0039-20240115","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.stem.2009.05.003","article-title":"Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti\u2010inflammatory protein TSG\u20106","volume":"5","year":"2009","journal-title":"Cell Stem Cell"},{"key":"lt24770-bib-0040-20240115","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/ni.2231","article-title":"Sensing and reacting to microbes through the inflammasomes","volume":"13","year":"2012","journal-title":"Nat Immunol"},{"key":"lt24770-bib-0041-20240115","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","year":"2010","journal-title":"Cell"},{"key":"lt24770-bib-0042-20240115","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.immuni.2012.03.012","article-title":"NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF\u2010\u03baB signaling","volume":"36","year":"2012","journal-title":"Immunity"},{"key":"lt24770-bib-0043-20240115","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1073\/pnas.1317643111","article-title":"Salmonella exploits NLRP12\u2010dependent innate immune signaling to suppress host defenses during infection","volume":"111","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"lt24770-bib-0044-20240115","first-page":"213","article-title":"The role of chemokines in acute liver injury","volume":"3","year":"2012","journal-title":"Front Physiol"},{"key":"lt24770-bib-0045-20240115","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1111\/ajt.13145","article-title":"Genomic profiles and predictors of early allograft dysfunction after human liver transplantation","volume":"15","year":"2015","journal-title":"Am J Transplant"},{"key":"lt24770-bib-0046-20240115","doi-asserted-by":"crossref","first-page":"e73054","DOI":"10.1371\/journal.pone.0073054","article-title":"Hepatocellular proliferation correlates with inflammatory cell and cytokine changes in a murine model of nonalchoholic fatty liver disease","volume":"8","year":"2013","journal-title":"PLoS One"},{"key":"lt24770-bib-0047-20240115","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1684\/ecn.2015.0359","article-title":"Intereukin\u201010 and Kupffer cells protect steatotic mice livers from ischemia\u2010reperfusion injury","volume":"25","year":"2014","journal-title":"Eur Cytokine Netw"},{"key":"lt24770-bib-0048-20240115","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1016\/S0016-5085(03)01209-5","article-title":"Apoptosis versus oncotic necrosis in hepatic ischemia\/reperfusion injury","volume":"125","year":"2003","journal-title":"Gastroenterology"},{"key":"lt24770-bib-0049-20240115","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1007\/BF02975251","article-title":"Role of Kupffer cells in cold\/warm ischemia\u2010reperfusion injury of rat liver","volume":"23","year":"2000","journal-title":"Arch Pharm Res"}],"container-title":["Liver Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Flt.24770","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01445473-201706000-00011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T01:39:40Z","timestamp":1705282780000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01445473-201706000-00011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,26]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/lt.24770","relation":{},"ISSN":["1527-6465","1527-6473"],"issn-type":[{"value":"1527-6465","type":"print"},{"value":"1527-6473","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,26]]}}}