Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response

Abstract

Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell‐based therapies. However, the efficacy and underlying mechanisms of EV‐based treatment in hepatic ischemia‐reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC‐EVs (huc‐MSC‐EVs) could protect against IRI‐induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc‐MSC‐EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress‐induced cell death in vitro. Interestingly, we found that the mitochondria‐located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc‐MSC‐EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc‐MSCs decreased the level of MnSOD in huc‐MSC‐EVs and attenuated the antiapoptotic and antioxidant capacities of huc‐MSC‐EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20‐tetrakis (4‐benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc‐MSC‐EVs on hepatic IRI and evaluate their preclinical application.—Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 33, 1695–1710 (2019). http://www.fasebj.org

Metabolic Nano-Machines: Extracellular Vesicles Containing Active Enzymes and Their Contribution to Liver Diseases

“…This review emphasizes the enzymatic activities that are present in cell-secreted EVs that present vesicles as truly circulating metabolic nano-machines able in a coordinated manner to carry specific activities in tissues that are distant from the tissues of origin. Although the impact of those activities in the body homeostasis is still unknown, what is known is that the acceptor cells will make use of the toolkit handled in the EVs' cargo [53,57]. With respect to liver diseases, this phenomenon could be of great importance, given the degree of specialization that this organ has in blood homeostasis, detoxification, and xenobiotic metabolism.…”

“…IRI is a severe injury caused by the interruption of blood flow to the liver and is characterized by inflammation and oxidative stress after ATP depletion [97]. In their study, the authors found that the enzyme MnSOD, which was encapsulated in human umbilical cord-derived mesenchymal stem cell EVS (huc-MSC-EVs), reduced oxidative stress in the hepatic IRI model [57]. This result again confirms that EVs could work as a therapeutic vehicle, giving capabilities to the acceptor cells that can be used in therapeutics.…”

Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

“…and manganese superoxide dismutase, which inhibited hepatocyte apoptosis induced by oxidative stress and protected against hepatic IRI in rats [74]. EVs produced from amniotic fluid stem cells could capture excess VEGF through VEGFR1 on their surface to protect against VEGF-induced glomerular endothelial cell apoptosis in mice [75].…”

“…Fetal liver MSC-EXs transport latency-associated peptides, TGF-β, and thrombospondin 1 to activate TGF-β/Smad2/3 signaling in natural killer (NK) cells and they also inhibit NK cell cytotoxicity in vitro, which implies a potential for the treatment of autoimmune diseases [79]. In a rat model of hepatic IRI, hucMSC-EV treatment protected against liver injury by reducing neutrophil inflammatory responses and oxidative stress [74].…”

“…Cells 2020, 9, x FOR PEER REVIEW 15 of 28 SC-EVs can protect against cell apoptosis that is induced by several factors and can reduce tissue damage. Yao et al revealed that hucMSC-EVs transported mitochondria-located antioxidant enzymes and manganese superoxide dismutase, which inhibited hepatocyte apoptosis induced by oxidative stress and protected against hepatic IRI in rats [74]. EVs produced from amniotic fluid stem cells could capture excess VEGF through VEGFR1 on their surface to protect against VEGF-induced glomerular endothelial cell apoptosis in mice [75].…”