*Purpose: Revascularization of the transplant islet is a crucial step that defines the success rate of patient recovery. Though bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization, its cellular mechanism remains unclear. The transcription factor, insulin gene enhancer binding protein-1 (ISL1), which is involved in islet cell proliferation also plays a potential regulatory role in the revascularization of islet cells. Our LC−MS/MS analyses results showed that BMSCs could promote the expression of ISL1 in islets. Hence, we set out to investigate the potential role of ISL1 in the revascularization process of islet transplantation.

*Methods: Pancreatic islets and BMSC were isolated from Lewis rats. Quantitative proteomic analysis with TMT labeling was conducted to evaluate the change of protein profiles between islets that were cultured with or without BMSCs. By using in vitro co-culturing system and rat diabetes model, we examined the function, revascularization and ISL1 expression in islets and in rat pancreatic β (INS-1) cells with or without co-cultured/co-transplanted with BMSCs. Furthermore, INS-1 cells were transfected with lentivirus that can elevate or inhibit ISL1 expression. Chromatin immunoprecipitation (ChIP) were used to investigate the potential correlation between ISL1 and vascular endothelial growth factor A (VEGFA).

*Results: Our LC−MS/MS data showed that the expression of ISL1 and VEGFA were significantly increased in the islets after it was co-cultured with BMSCs. The results from in vitro co-culturing system and rat diabetes model showed that the survival rate and insulin secretion from islets were increased with BMSCs were present, indicating that BMSCs promotes islet revascularization. We also observed that the presence of BMSCs led to an increase of ISL1 and VEGFA expression in both the islets and INS-1 cells. In silico protein structure modelling indicate that ISL1 is a transcription factor that has 4 binding sites with the mRNA of VEGFA. Further results showed that over-expression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, whilst inhibition of ISL1 decreased the abundance of VEGFA. CHIP-qPCR assay results indicated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells.

*Conclusions: Our results revealed that BMSCs promote the expression of ISL1 in islets and lead to an increase of VEGFA in grafted islets. Hence ISL1 is a potential target to induce early revascularization for islet transplantation.

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