Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
Stem Cells. 2021 Aug;39(8):1033-1048. doi: 10.1002/stem.3378. Epub 2021 Apr 3.
Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in islet transplantation.
胰岛移植的再血管化是决定患者康复成功率的关键步骤。骨髓间充质干细胞（BMSCs）已被报道可促进再血管化；然而，其潜在的细胞机制尚不清楚。此外，我们的液相色谱-串联质谱结果表明，BMSCs 可促进胰岛中胰岛素基因增强子结合蛋白-1（ISL1）的表达。ISL1 参与胰岛增殖，并在胰岛再血管化中发挥潜在的调节作用。本研究将 ISL1 蛋白鉴定为 BMSCs 介导的胰岛移植物再血管化的潜在调节剂。我们证明了在 BMSCs 存在的情况下，胰岛的存活率和胰岛素分泌增加，这表明 BMSCs 在共培养系统和大鼠糖尿病模型中促进胰岛再血管化。有趣的是，我们还观察到 BMSCs 的存在导致 ISL1 和血管内皮生长因子 A（VEGFA）在胰岛和 INS-1 大鼠胰岛素瘤细胞系中的表达增加。蛋白质结构的计算机模拟表明，ISL1 是一种转录因子，它与 VEGFA mRNA 有四个结合位点。进一步的结果表明，ISL1 的过表达增加了 VEGFA 转录物的丰度和蛋白积累，而 ISL1 的抑制减少了 VEGFA 的丰度。通过 ChIP-qPCR 检测，我们证明了 ISL1 和 VEGFA 之间在 INS-1 细胞中存在直接的分子相互作用。总之，这些发现表明，BMSCs 可促进胰岛中 ISL1 的表达，并导致胰岛移植物中 VEGFA 的增加。因此，ISL1 是诱导胰岛移植早期再血管化的潜在靶点。
