Exosomal MicroRNAs Derived From Umbilical Mesenchymal Stem Cells Inhibit Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) is a significant global public health problem, causing more than 350,000 deaths every year. Although the development of direct-acting antivirals has improved the sustained virological response rate in HCV patients, novel anti-HCV agents with higher efficacy as well as better tolerance and cheaper production costs are still urgently needed. Cell-based therapy, especially its unique and strong paracrine ability to transfer information to other cells via extracellular vesicles such as exosomes, has become one of the most popular therapeutic methods in recent years. In our study, exosomes secreted from umbilical mesenchymal stem cells (uMSCs), which are widely used in regenerative medicine, inhibited HCV infection in vitro, especially viral replication, with low cell toxicity. Our analysis revealed that microRNAs (miRNAs) from uMSC-derived exosomes (uMSC-Exo) had their unique expression profiles, and these functional miRNAs, mainly represented by let-7f, miR-145, miR-199a, and miR-221 released from uMSC-Exo, largely contributed to the suppression of HCV RNA replication. These four miRNAs possessed binding sites in HCV RNA as demonstrated by the target prediction algorithm. In addition, uMSC-Exo therapy showed synergistic effect when combined with U.S. Food and Drug Administration-approved interferon-a or telaprevir, enhancing their anti-HCV ability and thus improving the clinical significance of these regenerative substances for future application as optimal adjuvants of anti-HCV therapy. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1190-1203 SIGNIFICANCEThis work reported, for the first time, the identification of stem cell-derived exosomes of antiviral activity. Umbilical mesenchymal stem cell-secreted exosomes inhibited hepatitis C virus infection through transporting a mixture of microRNAs complementing the viral genomes to the host cells. This finding provides insights and prospects for physiologically secreted substances for antiviral therapy.

Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms

“…This is corroborated by protein analysis of BMSC exosomes that did not detect any candidate NTF among their cargo [22]. In contrast BMSC exosomes contain a variety of miRNA [55][56][57], many of which their function is currently unknown. One candidate is miR-17-92 which is located within BMSC-derived exosomes [32] and has been found to target and downregulate phosphatase and tensin homolog (PTEN) expression [32], an important suppressor of RGC axonal growth and survival [58,59].…”

Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model

“…In this study, the anti-influenza virus activity of MSC-EVs in lung epithelial cells was mediated by their mRNA content as pretreatment of EVs with RNase enzyme abrogated the anti-influenza virus activity of EVs. In a recent study, Qian and colleagues [41] demonstrated that exosomes (Exo) isolated from umbilical cord-derived MSCs inhibited replication of hepatitis C virus (HCV) in human dermal fibroblast 7 cells. These authors further identified four MSC-Exo-specific miRNAs with anti-HCV activity.…”

Concise Review: Extracellular Vesicles Overcoming Limitations of Cell Therapies in Ischemic Stroke

“…Although a direct comparison between these studies is not eligible due to different study designs, EVs might either have a direct impact on tumor formation or enhance sensitivity to chemotherapy [75,84,86,96]. Similar evidence for overlapping effects of EVs came from studies in inflammatory/infectious conditions, such as arthritis, hepatitis C, HIV, and sepsis [74,87,93,98,99]. One has to stress that several observations are still limited to in vitro research only.…”