Abstract:
Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are of interest as a new vector for the delivery of therapeutic agents into the tumor microenvironment. Cell-free EV-based therapy has a number of advantages over cell-based therapy, since the use of EVs allows avoiding potential undesirable transformation associated with MSCs. MSC-derived EVs can transfer natural proteins with immunomodulatory or antitumor properties. The aim of this study was to produce vesicles from mesenchymal stem cells with simultaneous overexpression of TRAIL, PTEN and IFN-β1 and analyze its antitumor and immunomodulatory properties. In this work, a stable line of human adipose tissue-derived mesenchymal stem cells (hADSCs) with simultaneous overexpression of TRAIL, PTEN and IFN-β1 was produced. To obtain this cell line hADSCs were genetically modified with a genetic multicistronic cassette encoding TRAIL, PTEN, and IFN-β1 genes separated with a self-cleaving P2A peptide nucleotide sequence. Membrane vesicles (CIMVs) were obtained from genetically modified hADSCs using cytochalasin B treatment. Antitumor and immunomodulatory properties of the CIMVs were analyzed in vitro. It was shown that CIMVs isolated from genetically modified hADSCs overexpressing TRAIL, PTEN and IFN-β1 genes are able to activate human immune cells and induce apoptosis in various types of carcinomas in vitro. Thus, the immunomodulatory and antitumor properties of CIMVs were shown. However, further studies on animal models in vivo are required.
