Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China.
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an, 710061, Shaanxi, China.
Cell Mol Life Sci. 2022 Oct 3;79(10):538. doi: 10.1007/s00018-022-04571-0.
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.
胰岛细胞移植早期细胞凋亡是影响胰岛移植疗效的主要因素之一。胰岛细胞与骨髓间充质干细胞（BMSCs）联合移植可显著提高移植后胰岛的存活率。转录因子胰岛素基因增强结合蛋白 1（ISL1）在共移植过程中被证明可以促进移植胰岛的血管生成和间充质干细胞的旁分泌功能，但调节机制尚不清楚。通过使用过表达 ISL1 的 BMSCs 和亚治疗剂量的胰岛进行共移植，我们成功地减少了移植物的凋亡并提高了其存活率。我们的代谢组学和蛋白质组学数据表明，ISL1 上调了苯胺（ANLN）和抑制素βA 链（INHBA），并刺激了 BMSCs 中咖啡因的释放。然后我们证明，ISL1 通过与这两个基因的启动子区域结合来上调 ANLN 和 INHBA 的表达。此外，ISL1 还可以促进 BMSCs 释放高表达 ANLN 的外泌体，分泌 INHBA 和咖啡因，并减少链脲佐菌素（STZ）诱导的胰岛细胞凋亡。因此，我们的研究为胰岛/BMSCs 共移植提供了机制上的见解，并为使用条件培养基模拟过表达 ISL1 的 BMSCs 共移植奠定了基础。
