Bone marrow‐derived mesenchymal stem cells improve rat islet graft revascularization by upregulating ISL1
Bone marrow‐derived mesenchymal stem cells improve rat islet graft revascularization by upregulating ISL1
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DOI：
10.1002/stem.3378
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发表时间：
2021-03
期刊：
影响因子：
5.2
通讯作者：
Ying Wang;Jingwen Wang;Yang Li;Xiao-hui Tian;Xin-shun Feng;Shuai Zhang;Peijun Liu;W. Xue;
中科院分区：
文献类型：
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作者：
Ying Wang;Jingwen Wang;Yang Li;Xiao-hui Tian;Xin-shun Feng;Shuai Zhang;Peijun Liu;W. Xue;
胰岛移植的血运重建是决定患者康复成功率的关键步骤。骨髓间充质干细胞（BMSCs）已被报道可促进血管再生;然而，其潜在的细胞机制仍不清楚。此外，我们的液相色谱-串联质谱结果表明，BMSCs可以促进胰岛中胰岛素基因增强子结合蛋白-1（ISL 1）的表达。ISL 1参与胰岛细胞的增殖，并在胰岛细胞的血管重建中发挥潜在的调节作用。这项研究确定了ISL 1蛋白作为BMSC介导的胰岛移植物血管重建的潜在调节剂。我们证明，在BMSCs存在下，胰岛的存活率和胰岛素分泌增加，表明BMSCs促进共培养系统和大鼠糖尿病模型中的胰岛血管重建。有趣的是，我们还观察到BMSC的存在导致胰岛和INS-1大鼠胰岛素瘤细胞系中ISL 1和血管内皮生长因子A（VEGFA）表达增加。计算机蛋白质结构建模表明，ISL 1是一种转录因子，与VEGFA mRNA有四个结合位点。进一步的结果表明，过表达ISL 1增加了VEGFA转录本和蛋白质积累的丰度，而抑制ISL 1则降低了VEGFA的丰度。使用ChIP-qPCR检测，我们证明了INS-1细胞中ISL 1和VEGFA之间的直接分子相互作用。总之，这些发现揭示了BMSC促进胰岛中ISL 1的表达，并导致胰岛移植物中VEGFA的增加。因此，ISL 1是诱导胰岛移植早期血管重建的潜在靶点。
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.