Mesenchymal stem cells protect against sepsis-associated acute kidney injury by inducing Gal-9/Tim-3 to remodel immune homeostasis

Abstract

Objective

The present study investigated the specific mechanism by which mesenchymal stem cells (MSCs) protect against sepsis-associated acute kidney injury (SA-AKI).

Methods

Male C57BL/6 mice underwent cecal ligation and puncture surgery to induce sepsis and then received either normal IgG or MSCs (1 × 10⁶ cells, intravenously) plus Gal-9 or soluble Tim-3 3 h after surgery.

Results

After cecal ligation and puncture surgery, the mice injected with Gal-9 or MSCs plus Gal-9 had a higher survival rate than the mice in the IgG treatment group. Treatment with MSCs plus Gal-9 decreased serum creatinine and blood urea nitrogen levels, improved tubular function recovery, reduced IL-17 and RORγt levels and induced IL-10 and FOXP3 expression. Additionally, the Th17/Treg cell balance was altered. However, when soluble Tim-3 was used to block the Gal-9/Tim-3 pathway, the septic mice developed kidney injury and exhibited increased mortality. Treatment with MSCs plus soluble Tim-3 blunted the therapeutic effect of MSCs, inhibited the induction of Tregs, and suppressed the inhibition of differentiation into Th17 cells.

Conclusion

Treatment with MSCs significantly reversed the Th1/Th2 balance. Thus, the Gal-9/Tim-3 pathway may be an important mechanism of MSC-mediated protection against SA-AKI.

Keywords:

• Mesenchymal stem cells
• sepsis-associated acute kidney injury
• Gal-9/Tim-3
• immune homeostasis

Acknowledgements

All authors read and approved the final manuscript. All authors consent for publication. A preprint has previously been published.

Authors contributions

Congjuan Luo and Yan Xu generated the hypothesis; Congjuan Luo, Feng Luo, Xiaofei Man, Quandong Bu, Haiyan Zhou and Long Zhao participated in study design and coordination; Congjuan Luo, Bin Zhou, Hui zhang, Wei Zhang, Hong Luan and Lin Che performed the experiments; Congjuan Luo subjected the mice to behavioral tasks during the experimental period; Feng Luo and Congjuan Luo performed the statistical analysis; Congjuan Luo and Feng Luo wrote the manuscript; and Feng Luo and Yan Xu made critical revisions to the manuscript.

Ethical approval

All the experimental procedures were performed with the approval of the Experimental Research Institute of the QingDao University and followed the guidelines of the Institutional Animal Care and Use Committee.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by a grant from the Fund of National Natural Science Foundation of China (81700585, 81800601, 81770679), and the Innovation Program of Qingdao Science and Technology (19-6-2-52-cg). Supported by Qingdao Key Health Discipline Development Fund.