Abstract
BACKGROUND: Vascular injury is one of the most common detrimental effects of cancer radiotherapy on healthy tissues. Since the efficacy of current preventive and therapeutic strategies remains limited, the exploration of new approaches to treat radiation-induced vascular injury (RIV) is on high demands. The use of mesenchymal stem cells (MSCs) to treat RIV holds great promise thanks to their well-documented function of mediating tissue regeneration after injury. Recently, we genetically modified MSCs with high mobility group box 1 (HMGB1) and demonstrated the high efficacy of these cells in treating graft atherosclerosis. The current study was to investigate the protective effect of HMGB1-modified MSCs (MSC-H) on RIV by using a rat model. METHODS: Female F344 rats received an intravenous injection of male F344 MSC-H cells or vehicle control at four doses of 2 × 10(6) cells with a 15-day interval starting from 30 days after irradiation to the abdominal aorta. The aortas were procured for histological and biomedical analysis at 90 days after irradiation. Cell migration to irradiated aortas was traced by green fluorescent protein and sex determination region on the Y chromosome. In vitro cell migration and endothelial differentiation of MSC-H cells were analyzed by stromal-derived factor 1-induced transwell assay and RNA microarray, respectively. The contribution of extracellular HMGB1 to the bioactivity of MSC-H cells was investigated by inhibition experiments with HMGB1 antibody. RESULT: MSC-H cell infusion alleviated neointimal formation, vascular inflammation, and fibrosis in irradiated aortas, which was associated with local migration and endothelial differentiation of MSC-H cells. The MSC-H cells showed high motility and potential of endothelial differentiation in vitro. Microarray analysis suggested multiple pathways like MAPK and p53 signaling were activated during endothelial differentiation. MSC-H cells highly expressed CXC chemokine receptor 4 and migrated progressively after stromal-derived factor 1 stimulation, which was blocked by the antagonist of CXC chemokine receptor 4. Finally, the migration and endothelial differentiation of MSC-H cells were inhibited by HMGB1 antibody. CONCLUSION: MSC-H cell infusion significantly attenuated RIV, which was associated with their high motility and endothelial differentiation potential. Multiple pathways that possibly contributed to the efficacy of MSC-H cells were suggested and deserved further investigation.