Emerging Roles Of Human Umbilical Cord Mesenchymal Stem Cells Derived Extracellular Vesicles On Schistosoma Japonicum Induced Liver Injury And The Safety Evaluation Of Tumor Promotion

Although mesenchymal stem cells(MSC)has potential therapeutic effect on a variety of diseases,including schistosoma japonicum(S.japonicum),there are still concerns that MSC might trigger pulmonary embolism and tumorigenicity in clinical settings.Extracellular vesicles(EVs)are nanoscale membranous vesicles constitutively secreted by almost all cell types.Accumulating evidence shows that EVs produced by MSC exert their therapeutic effects in several disease models,however,the roles of MSC-EVs in S.japonicum infection in unknown.In addition,many studies have found that MSC can affect tumor progression by acting on tumor cells in paracrine form.EVs is an important part of paracytic secretion,thus it is necessary to explore the role of MSC-EVs in tumor,not only reveal the mechanism of MSC on tumor,but also provide data for clinical safety of MSC-EVs.Based on this,this study is divided into two parts: 1.Emerging roles of human umbilical cord mesenchymal stem cells derived extracellular vesicles on Schistosoma japonicum induced liver granuloma and fibrosis;2.Effect and mechanism of h UCMSC-EVs on lung adenocarcinoma growth.1.Emerging roles of human umbilical cord mesenchymal stem cells derived extracellular vesicles on Schistosoma japonicum induced liver granuloma and fibrosisHere we investigated the therapeutic potential of human umbilical cord MSCEVs(h UCMSC-EVs)using our established mouse models for S.japonicum infection.The data demonstrated that h UCMSC-EVs could effectively prolong the survival time of infected mice and alleviate liver granuloma and fibrosis.In addition,h UCMSC-EVs had therapeutic effect on hepatic fibrosis.We also found that h UCMSC-EVs could migrate to the infected mice liver and inhibit the activation of hepatic stellate cells(HSC)and collagen production.HUCMSC-EVs significantly inhibited the activity and proliferation of human hepatic stellate cell line LX-2 and TGF-?1-mediated HSC collagen production in vitro.HUCMSC-EVs reduced IL-4levels in the liver and serum of infected mice,as well as the number of Th2 cells.These result suggest that h UCMSC-EVs may be an alternative to cell therapy for schistosomiasis and may have therapeutic effect on other liver fibrosis and Th2-induced immune diseases.2.Effect and mechanism of h UCMSC-EVs on lung adenocarcinoma growthWe demonstrated for the first time that h UCMSCs dramatically increased the growth of lung adenocarcinoma(LUAD)cancer cells in a xenograft tumor model.Then,we observed that h UCMSC-EVs contribute to the h UCMSC-promoted LUAD cell growth through a direct effect on LUAD cells.Furthermore,we showed that h UCMSC-EV-mediated LUAD growth is associated with increased proliferation and decreased apoptosis in LUAD cells,concomitant with reduced PTEN expression mediated by the h UCMSC-EV-transmitted mi R-410.Our findings provide novel insights into the intercellular communications between cancer cells and MSCs through MSC-EV-mi RNA and suggest that modification of h UCMSC-EVs might be an attractive therapeutic option for the clinical application of h UCMSC-EVs that would reduce unwanted side effects.