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Exosomes Secreted by Mesenchymal Stem Cells Induce Immune Tolerance to Mouse Kidney Transplantation via Transporting LncRNA DANCR

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Abstract—

Mesenchymal stem cells induce kidney transplant tolerance by increasing regulatory T (Treg) cells. Bone marrow mesenchymal stem cell exosomes (BMMSC-Ex) promote Treg cell differentiation. Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is expressed in BMMSCs and can be encapsulated in exosomes. We aimed to explore the role of DANCR in BMMSC-Ex in immune tolerance after kidney transplantation and related mechanism. The isogenic/allograft kidney transplantation mouse model was established, and levels of serum creatinine (SCr) were determined. Hematoxylin–eosin staining was conducted to detect the inflammation, and immunohistochemistry was performed to detect the infiltration of CD4+ T cells. Levels of IFN-γ, IL-17, and IL-2 were examined by ELISA. Flow cytometry was conducted to determine Treg cells. In the allograft group, the inflammatory response was severe, CD4+ T cell infiltration, SCr levels, and plasma rejection-related factors were up-regulated, while injection of BMMSC-Ex reversed the results. BMMSC-Ex increased Treg cells in kidney transplantation mice. Interference with DANCR reversed the promoting effect of BMMSC-Ex on Treg cell differentiation. DANCR bound to SIRT1, promoted ubiquitination and accelerated its degradation. The injection of BMMSC-Ex (after interference with DANCR) promoted SIRT1 levels, inflammatory response, CD4+ T cell infiltration, SCr levels, and plasma rejection related factors’ expression, while Treg cells were decreased. LncRNA DANCR in BMMSC-Ex promoted Treg cell differentiation and induced immune tolerance of kidney transplantation by down-regulating SIRT1 expression in CD4+ T cells.

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Funding

This study was supported by the foundation of Medical Science and Technology of Henan Province, No. LHGJ20200046.

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Authors and Affiliations

  1. Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China

    Xiaoqiang Wu, Zhiwei Wang, Junpeng Wang, Xiangyong Tian, Guanghui Cao & Tianzhong Yan

  2. Department of Nephrology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, 450003, Henan, China

    Yue Gu & Fengmin Shao

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  1. Xiaoqiang Wu
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Contributions

XW and TY put forward the concept of the study, designed the study, prepared the manuscript, and contributed to the statistical analysis. ZW and JW contributed to the data acquisition. XT and GC contributed to the quality control of data and algorithms. YG analyzed the data and interpretation. FS edited the manuscript. TY put forward the concept of the study, contributed to the data analysis and interpretation, and reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Tianzhong Yan.

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Our study was approved by Zhengzhou University People’s Hospital. The experimental procedures were approved by the Medical Ethics review committee of Zhengzhou University People’s Hospital.

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The study was undertaken with the patient’s consent.

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The authors declare no competing interests.

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Wu, X., Wang, Z., Wang, J. et al. Exosomes Secreted by Mesenchymal Stem Cells Induce Immune Tolerance to Mouse Kidney Transplantation via Transporting LncRNA DANCR. Inflammation 45, 460–475 (2022). https://doi.org/10.1007/s10753-021-01561-5

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