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BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine

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Abstract

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.

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Acknowledgements

The authors thank Bing Liu (BioBank, the First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi Province, China) for technical help and revising the manuscript.

Funding

The project was supported by the National Natural Science Foundation of China (no. 81970670, 81970668, 82103213, and 82170768) and the Natural Science Foundation of Shaanxi Province (no. 2020JM-372).

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  1. Ying Wang and Jiang-Wei Zhang contributed equally to this work.

Authors and Affiliations

  1. 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

    Ying Wang, Jiang-Wei Zhang, Jing-Wen Wang, Jia-Le Wang, Shu-Cong Zhang, Rui-Yang Ma, Jing Zhang, Yang Li, Wu-Jun Xue, Jin Zheng & Xiao-Ming Ding

  2. Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an, 710061, Shaanxi, China

    Pei-Jun Liu

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Contributions

YW and X-MD developed the concept, designed experiments, and interpreted the data. YW, J-WZ, J-WW, J-LW, R-YM and S-CZ, conducted experiments and collected data. YW and J-WW analyzed data. YW, J-WZ, and X-MD prepared the manuscript. YW, P-JL, J-WZ, J-WW, J-LW, and X-MD made revisions to the manuscript. All the authors approved the final content. YW and X-MD are the guarantors of this work and, as such, had full access to all the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Xiao-Ming Ding.

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All animal procedures were approved by the Xi'an Jiaotong University Animal Experimentation Ethics Committee.

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18_2022_4571_MOESM1_ESM.docx

ANLN carrying exosome, INHBA, and caffeine reduce the apoptosis of grafted islets during BMSC overexpressing ISL1 co-transplantation, Supplementary Figures S1–5 and Tables S1–4. (DOCX 3541 KB)

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Wang, Y., Zhang, JW., Wang, JW. et al. BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine. Cell. Mol. Life Sci. 79, 538 (2022). https://doi.org/10.1007/s00018-022-04571-0

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