Exosomes are small biological membrane vesicles secreted by various cells, including mesenchymal stem cells (MSCs). We previously reported that MSC-derived exosomes (MSC-Ex) can elicit hepatoprotective effects against toxicant-induced injury. However, the success of MSC-Ex-based therapy for treatment of liver diseases and the underlying mechanisms have not been well characterized. We used human umbilical cord MSC-derived exosome (hucMSC-Ex) administrated by tail vein or oral gavage at different doses and, in engrafted liver mouse models, noted antioxidant and anti-apoptotic effects and rescue from liver failure. A single systemic administration of hucMSC-Ex (16 mg/kg) effectively rescued the recipient mice from carbon tetrachloride (CCl 4 )-induced liver failure. Moreover, hucMSC-Ex-derived glutathione peroxidase1 (GPX1), which detoxifies CCl 4 and H 2 O 2 , reduced oxidative stress and apoptosis. Knockdown of GPX1 in hucMSCs abrogated antioxidant and anti-apoptotic abilities of hucMSC-Ex and diminished the hepatoprotective effects of hucMSC-Ex in vitro and in vivo. Thus, hucMSC-Ex promote the recovery of hepatic oxidant injury through the delivery of GPX1.

BackgroundThe invasive nature of liver biopsy makes the histopathological diagnosis of non-alcoholic fatty liver disease (NAFLD) difficult and its diagnostic performance unsatisfactory. The present study aimed to identify a serum microRNA (miRNA) expression profile that could serve as a novel diagnostic biomarker for NAFLD.MethodsSerum miRNA expression was investigated using three cohorts comprising 465 participants (healthy controls and NAFLD patients) recruited between August 2010 and June 2013. miRNA expression was initially screened by Illumina sequencing using serum samples pooled from 20 patients and 20 controls. Quantitative reverse transcriptase polymerase chain reaction assay was then used to evaluate the expression of selected miRNAs. A logistic regression model was constructed using a training cohort (n = 242) and validated using another cohort (n = 183). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy.ResultsWe identified an miRNA panel (hsa-miR-122-5p, hsa-miR-1290, hsa-miR-27b-3p, and hsa-miR-192-5p) with a high diagnostic accuracy for NAFLD. The satisfactory diagnostic performance of the miRNA panel remained regardless of the NAFLD activity score (NAS) status. There was significant difference between the AUC values of the miRNA panel and those of ALT (AUC = 0.786, 95% CI = 0.717–0.855; P = 0.142) and FIB-4 (AUC = 0.795, 95% CI = 0.730–0.860; sensitivity = 69.9%, specificity = 83.7%.ConclusionWe identified a serum microRNA panel with considerable clinical value in NAFLD diagnosis. The results indicate that the miRNA panel is a more sensitive and specific biomarker for NAFLD than ALT and FIB-4.

Nevertheless, a study by Yu et al. has revealed that another combination of four factors (Oct3/4, Sox2, NANOG [Nanog ho-meobox], and LIN28 [lin-28 homolog]) is also sufficient to induce pluripotent stem cells from human somatic cells, 4 indicating that more genes are involved in the establishment or maintenance of pluripotency. In this case, the therapy of HCC directing to one or several of these genes may be insufficient to achieve satisfactory efficacy. On the other hand, a recent report by Gupta et al. showed that salinomycin might selectively eliminate breast CSCs and inhibit metastasis by inducing the differentiation of CSCs. They also suggest that it is preferable to treat cancer using agents that target both the CSCs and non-CSCs, because non-CSCs might transform into CSCs and thus eradication of CSCs alone may not obtain complete regression of an established tumor. 5 Interestingly, our study indicated that HNF4 could induce the differentiation of both hepatoma cells and its CSCs. The suppression of CSCs was accompanied by the inhibition of a cluster of genes which contribute to the pluripotency of human stem cells, including-catenin, Oct3/4, SMO(smoothened homolog), Bmi, Sox2, NANOG, c-Myc, Klf4, LIN28, and ESG1 (enhancer of split groucho 1). 3 More recently, we also demonstrated that up-regulation of HNF4 remarkably ameliorated hepatic fibrosis 6 and prevented the development of HCC in rats accompanied by the revision of epithelial-mesenchymal transition (unpublished data). Thus, we believe that differentiation therapy with HNF4, a central regulator for hepatocyte differentiation, might be an ideal strategy for the treatment of human HCC. Moreover, this strategy may be extended to other cancer types through the induction of differentiation using their corresponding key transcription factors.

Mesenchymal stem cells (MSCs) have been increasingly applied into clinical therapy. Exosomes are small (30–100 nm in diameter) membrane vesicles released by different cell types and possess the similar functions with their derived cells. Human umbilical cord MSC-derived exosomes (hucMSC-Ex) play important roles in liver repair. However, the effects and mechanisms of hucMSC-Ex on liver injury development remain elusive. Mouse models of acute and chronic liver injury and liver tumor were induced by carbon tetrachloride (CCl4) injection, followed by administration of hucMSC-Ex via the tail vein. Alleviation of liver injury by hucMSC-Ex was determined. We further explored the production of oxidative stress and apoptosis in the development of liver injury and compared the antioxidant effects of hucMSC-Ex with frequently used hepatic protectant, bifendate (DDB) in liver injury. hucMSC-Ex alleviated CCl4-induced acute liver injury and liver fibrosis and restrained the growth of liver tumors. Decreased oxidative stress and apoptosis were found in hucMSC-Ex-treated mouse models and liver cells. Compared to bifendate (DDB) treatment, hucMSC-Ex presented more distinct antioxidant and hepatoprotective effects. hucMSC-Ex may suppress CCl4-induced liver injury development via antioxidant potentials and could be a more effective antioxidant than DDB in CCl4-induced liver tumor development.