Hepatic ischemia-reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSC) 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 MSCs (MSC-EV) on tissue injury. The effects of systemically administered mouse bone marrow derived MSC-EV were evaluated in an experimental murine model of hepatic IRI induced by cross clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of upto 6 hours. Compared with controls, intravenous administration of MSC-EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase-3 positive and apoptotic cells, and reduced serum aminotransferase levels. MSC-EV increased hepatic mRNA expression of NACHT, LRR and PYD domains-containing protein 12 (Nlrp12), and the chemokine (C-X-C motif) ligand 1 (CXCL1), and reduced mRNA expression of several inflammatory cytokines such as IL-6 during IRI. MSC-EV increased cell viability and suppressed both oxidative injury and NF-κB activity in AML12 murine hepatocytes in vitro. In conclusion, the administration of EV derived from bone marrow derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.

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Current approaches for collection of extracellular vesicles (EV) are based on classical cell culture media production. This involves collection from cells grown in flasks, and can require multiple rounds of centrifugation or filtration, followed by ultracentrifugation or density gradient centrifugation. There are several limitations of these approaches, for example, they require a large input volume, the yield and concentration is low, and the process is time consuming. Most cell cultures require the use of fetal bovine serum which contains a large amount of endogenous EV that can contaminate isolations of cell-derived EVs. The use of cell cultures within a hollow fiber bioreactor could address many of these limitations and produce a continuous source of highly concentrated EVs without contamination from serum EVs, and that are suitable for downstream applications.