Purpose: Deficient angiogenesis in the early stage of islets transplantation is one of the main obstacles to its clinical application. Several studies have confirmed that co-transplantation of bone marrow mesenchymal stem cells (BMSCs) and islets can improve the angiogenesis in early transplanted islets, but the mechanism remaining further characterized. Islet-1 (Isl1) is a (LIM)-homeodomain transcription factor important for pancreatic islet cells development, maturation, and function.Importantly Isl1 can enhance the release of vascular endothelial growth factor-a (VEGF-A) in human umbilical vein endothelial cells and plays a vital role in angiogenesis. The aim of this study was to investigate whether upregulation of Isl1expression in islets co-cultured with BMSCs improved the poor angiogenesis in the early stage of islets transplantation.
Methods: Primary islet cells isolated from Lewis rats and rat β cell line (INS-1) were cultured with or without BMSCs for 48 hours respectively, and then the islets function was detected by  glucose-stimulated insulin secretion (GSIS). Viability of islets was measured using fluorescein diacetate and PI staining. The apoptosis assay of islets was performed by cytometry. Quantitative RT-PCR, immunoblot and immunofluorescence were enrolled to examine the mRNA and protein expression of Isl1 and VEGF-A of primary islet cells or INS-1 in co-culture and culture groups.Besides, we used lentiviral vector, GV358-Isl1, to increase Isl1 in INS-1 and corroborated the increase of Isl1,activator of the nuclear factor-kappa B (NF-κB) and VEGF protein levels by immunoblot analysis.
Results: Co-culture of rat islet cells with BMSCs can improve rat survival rate and maintain glucose-induced insulin secretion. Though BMSCs cannot improve the loss of intraislet endothelial cells in early islet cells, it can reduce the early apoptosis rate of islet cells.Importantly, co-culture with BMSCs provoked both the mRNA and protein expressions of Isl1 and induced the expression of VEGF-A in islet cells.Our further study found that Isl1 overexpression of INS-1 greatly enhanced expression of NF-κB p65 and VEGF-A. 
Conclusion: Co-culture with BMSCs could induce the expression of ISL1 in islets, which promote angiogenesis by NF-κB pathways and ultimately ameliorate ischemia and hypoxia to improve the graft's activity and survival rate.