SC-24 * IMPROVEMENT OF HUMAN MESENCHYMAL STEM CELL HOMING IN DELIVERY OF THERAPEUTIC AGENTS TO GLIOMA STEM CELL XENOGRAFTS

Abstract

There is an urgent need to develop novel delivery methods for brain tumors. To this end, we have developed human bone marrow mesenchymal stem cells (MSCs) to overcome the problems associated with traditional therapeutic treatments. Compared with other cellular delivery systems, MSCs may be easily acquired from patients, can be readily expanded and engineered ex vivo, can be auto-transfused without fear of rejection, and are free of ethical concerns. Therefore, MSCs are the ideal cells for therapeutic clinical applications. Defining the process of homing of MSCs to tumors-which is largely unknown-is essential to improve their application in clinical medicine. We have recently exploited glioma stem cell (GSC) xenografts (GSCXs) as a pertinent clinical model of human gliomas, because unlike GBM cell lines, GSCXs recapitulate the histology of the tumor from which they are derived. After intravascular delivery some GSCXs attract MSCs, while others do not. We hypothesized that successful homing of MSCs to GSCXs requires chemoattraction, adhesion to the endothelial wall, and extravasation. Adhesion and extravasation are driven largely by lectin-carbohydrate interactions. Measurements of MSC and GSCX glycogene expression, glycan expression on cell surface proteins, and quantitative proteomics were performed. We compared the molecular landscapes of attracting vs. non-attracting GSCXs. Key findings were the shift from high-mannose type glycosylation on MSCs following exposure to chemoattractants and expression of SIGLEC9 by attractor GSCXs versus expression of SIGLEC8 in non-attractors. Attractor GSCXs displayed down-regulated galactosyltransferase activity, whereas non-attractors were enriched in transcripts related to mannosyltransferases. In attractor GSCXs, kallikrein 4, 13, 14, and 15 were upregulated. These serine proteases are likely to contribute to the modulation of the tumoral extracellular biochemical environment. Results from this project will lead to future engineering strategies to enhance engraftment of MSCs in gliomas, a concept that is likely to have great clinical benefit.