BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine
BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine
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DOI：
10.1007/s00018-022-04571-0
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发表时间：
2022-10
影响因子：
8
通讯作者：
Ying Wang;Jiang-wei Zhang;Jingwen Wang;Jia-le Wang;Shuai Zhang;Ruilian Ma;Jing Zhang;Yang Li-Yang-L
中科院分区：
文献类型：
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作者：
Ying Wang;Jiang-wei Zhang;Jingwen Wang;Jia-le Wang;Shuai Zhang;Ruilian Ma;Jing Zhang;Yang Li-Yang-L
移植胰岛的早期凋亡是影响胰岛移植效果的主要因素之一。胰岛细胞与骨髓间充质干细胞联合移植可显著提高移植胰岛的存活率。转录因子胰岛素基因增强子结合蛋白1（insulin gene enhancer binding protein 1，ISL 1）在共移植过程中促进移植胰岛血管生成和间充质干细胞的旁分泌功能，但其调控机制尚不清楚。通过使用过度表达ISL 1的BMSCs和亚治疗剂量的胰岛进行共移植，我们设法减少了细胞凋亡，提高了移植物的存活率。我们的代谢组学和蛋白质组学数据表明，ISL 1上调苯胺（ANLN）和抑制素β A链（INHBA），并刺激BMSCs中咖啡因的释放。然后，我们证明了ANLN和INHBA的上调是通过ISL 1与这两个基因的启动子区域的结合实现的。此外，ISL 1还能促进BMSCs释放高表达ANLN的exosomes，分泌INHBA和咖啡因，减少STZ诱导的胰岛细胞凋亡。因此，我们的研究为胰岛/BMSCs共移植提供了力学见解，并为使用条件培养基模拟ISL 1过表达的BMSCs共移植奠定了基础。
Early apoptosis of grafted islets is one of the main factors affecting the efficacy of islet transplantation. The combined transplantation of islet cells and bone marrow mesenchymal stem cells (BMSCs) can significantly improve the survival rate of grafted islets. Transcription factor insulin gene enhancer binding protein 1 (ISL1) is shown to promote the angiogenesis of grafted islets and the paracrine function of mesenchymal stem cells during the co-transplantation, yet the regulatory mechanism remains unclear. By using ISL1-overexpressing BMSCs and the subtherapeutic doses of islets for co-transplantation, we managed to reduce the apoptosis and improve the survival rate of the grafts. Our metabolomics and proteomics data suggested that ISL1 upregulates aniline (ANLN) and Inhibin beta A chain (INHBA), and stimulated the release of caffeine in the BMSCs. We then demonstrated that the upregulation of ANLN and INHBA was achieved by the binding of ISL1 to the promoter regions of the two genes. In addition, ISL1 could also promote BMSCs to release exosomes with high expression of ANLN, secrete INHBA and caffeine, and reduce streptozocin (STZ)-induced islets apoptosis. Thus, our study provides mechanical insight into the islet/BMSCs co-transplantation and paves the foundation for using conditioned medium to mimic the ISL1-overexpressing BMSCs co-transplantation.Graphical abstract