Extracellular vesicles from bone marrow–derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury

Abstract

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.

Therapeutic effects of serum extracellular vesicles in liver fibrosis

“…Migratory responses and expression of activation markers in HSC are also stimulated by exosomes from, respectively, endothelial cells or other activated HSC [62,63]. In these prior studies, the observed responses were attributed to the uptake into the recipient cells and subsequent action of a variety of EV cargo molecules including CXCL10 [58] S1P [59,64], TRAIL [32], vanin-1 [60], CD40L [57], SK1/2[59,64], CCN2[25] or miRs [26]. An important feature of many of these findings is that the pathophysiology-related pathways were driven by EVs derived from cells that were injured (e.g.…”

Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA

“…EVs derived from mesenchymal stem cells (MSCEVs) have been shown to improve the survival of mice with d‐galactosamine/TNF‐α‐induced lethal hepatic failure . MSCEVs have also been shown to be a protective treatment when administered before ischemic‐reperfusion liver injury in mice . Additionally, MSCEVs that contained the miRNA miR‐223 have been shown to have a protective effect in an experimental hepatitis mouse model as well .…”

Mesenchymal stem cell derived extracellular vesicles: a promising new therapeutic approach for hepatic injury

“…Human MSCs can be obtained from bone marrow, umbilical cord, adipose tissues or other adult human tissues (5). Most studies to date have been based on the use of bone marrow derived MSC.…”

“…In another study carried out by the same group, a protective effect of BM-MSC-EV was observed with experimental hepatic ischemia/ reperfusion injury in vivo . The administration of MSC-EV in mice after 6-hours of reperfusion, reduced serum markers of hepatic injury, blood urea nitrogen and creatinine, and decreased caspase 3—positive cells (5). Similarly, Tan et al .…”

“…A particular advantage of the use of MSC-EV over MSC is they do not carry the risk of pathological differentiation of engrafted cells that can occur with latter. Other potential benefits include long- term storage stability, ease of being internalized into recipient cells, very low immune rejection, and convenience of administration (5,20). Along with the results of these emerging studies showing beneficial effects in different models of hepatic injury, these advantages provide the impetus for further characterization of MSC-EV towards their use as a novel therapeutic approach to ameliorate hepatic injury.…”