Small extracellular vesicles encapsulating lefty1 mRNA inhibit hepatic fibrosis

Extracellular Vesicles

Liver fibrosis is the deposition of extracellular matrix (ECM) in the liver caused by persistent chronic injury, which can lead to more serious diseases such as cirrhosis or cancer. Blocking the effect of transforming growth factor β1 (TGF-β1), one of the most important cytokines in liver fibrosis, may be one of the effective ways to inhibit liver fibrosis. As a kind of natural nano-scale vesicles, small extracellular vesicles (sEvs) have displayed excellent delivery vehicle properties. Herein, we prepared hepatic stellate cell (HSC)-derived sEvs loading left-right determination factor 1 (lefty1) mRNA (sEvLs) and we wanted to verify whether they can inhibit fibrosis by blocking the TGF-β1 signaling pathway. The results showed that sEvLs had effective cell uptake and reduced activation of HSCs. Rats that were injected with CCl4 by intraperitoneal injection for 6 weeks exhibited obvious symptoms of liver fibrosis and were treated with systemically administered sEvLs and free sEvs for 4 weeks. Rats injected with olive oil alone served as sham controls. Administration of sEvLs significantly reduced the area of fibrosis compared with free sEvs. We demonstrated that sEvLs inhibited HSCs activation and ECM production, and promote ECM degradation by downregulating α-smooth muscle actin (α-SMA), collagen I, tissue inhibitor of metalloproteinase (TIMP) -1 and upregulating matrix metalloprotease (MMP) -1. In , as an endogenous delivery vehicle, sEvs could deliver mRNA to attenuate hepatic fibrosis by blocking the TGF-β/Smad signaling pathway.

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Recent Publications

Cigarette smoke (CS) represents one of the most relevant environmental risk factors for several chronic pathologies. Tissue damage caused by CS exposure is mediated, at least in part, by oxidative stress induced by its toxic and pro-oxidant components. Evidence demonstrates that extracellular vesicles (EVs) released by various cell types exposed to CS extract (CSE) are characterized by altered biochemical cargo and gained pathological properties. In the present study, we evaluated the content of oxidized proteins and phospholipid fatty acid profiles of EVs released by human bronchial epithelial BEAS-2B cells treated with CSE. This specific molecular characterization has hitherto not been performed. After confirmation that CSE reduces viability of BEAS-2B cells and elevates intracellular ROS levels, in a dose-dependent manner, we demonstrated that 24 h exposure at 1% CSE, a concentration that only slight modifies cell viability but increases ROS levels, was able to increase carbonylated protein levels in cells and released EVs. The release of oxidatively modified proteins via EVs might represent a mechanism used by cells to remove toxic proteins in order to avoid their intracellular overloading. Moreover, 1% CSE induced only few changes in the fatty acid asset in BEAS-2B cell membrane phospholipids, whereas several rearrangements were observed in EVs released by CSE-treated cells. The impact of changes in acyl chain composition of CSE-EVs accounted for the increased saturation levels of phospholipids, a membrane parameter that might influence EV stability, uptake and, at least in part, EV-mediated biological effects. The present in vitro study adds new information concerning the biochemical composition of CSE-related EVs, useful to predict their biological effects on target cells. Furthermore, the information regarding the presence of oxidized proteins and the specific membrane features of CSE-related EVs can be useful to define the utilization of circulating EVs as marker for diagnosing of CS-induced lung damage and/or CS-related diseases.

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