The Differentiation Of Mesenchymal Stem Cells To Vascular Cells Regulated By The HMGB1/RAGE Axis And Its Application In Transplant Arteriosclerosis

Background: Mesenchymal stem cell(MSC)transplantation brings new promise for the treatment of graft arteriosclerosis by promoting endothelial regeneration.However,its efficacy and safety are still under investigation.In particular,it has recently been discovered that neointimal smooth muscle cells are derived from MSC-like cells.The high mobility group box 1(HMGB1)/ receptor for advanced glycation end-product(RAGE)axis is involved in regulating the migration and differentiation of MSCs,therefore,it is speculated that could be used to improve the effect of cell therapy.Objective: The purpose of our study was to investigate this hypothesis.Methods: Rat MSCs were modified with HMGB1 cytokines or HMGB1 lentiviral vectors to activate the HMGB1 / RAGE axis.RAGEs were targeted and suppressed by specific RNA vectors.We evaluated the ability of the migration and differentiation of MSCs transfected in vitro and the transfected MSCs that transplanted in transplantation arteriosclerosis rat model.The differentiation of MSC into endothelial cells and smooth muscle cells were evaluated via measuring the expression levels of ?-smooth muscle actin(?SMA)and CD31.Results: Treatment of Exogenous HMGB1 cytokine and transfection of HMGB1 lentiviral vector could promote migration of MSC and could synergize with vascular endothelial growth factor(VEGF)to induce the differentiation of MSC into CD31 + cells,while inhibited the differentiation of MSCs into ?-SMA + cells regulated by platelet-derived growth factor(PDGF).These effects could be blocked by RAGE knockdown.HMGB1-modified cells preferentially migrated to the neointima of the graft and differentiated into CD31+ cells,while significantly alleviating transplant arteriosclerosis and inhibiting the expression levels of HMGB1 and RAGE in grafts.RAGE knockdown inhibited migration of cell to the graft vessel.Conclusions: HMGB1 stimulated the migration of MSCs and regulate the differentiation of MSCs into endothelial cells via the RAGE signaling pathway,and inhibited the differentiation of MSCs into smooth muscle cells,which in turn inhibited graft arteriosclerosis.We have transformed it into a successful application for cell therapy in transplant arteriosclerosis.