Abstract
Renal ischemia/reperfusion (I/R) injury is an inevitable consequence of kidney transplantation and can lead to fibrosis and graft failure. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for I/R injury. In this study, using a murine model of renal I/R injury, we demonstrated that administration of both syngeneic and allogeneic MSCs significantly ameliorated I/R injury. Treatment efficacy of MSCs could be attributed to inhibited I/R-induced infiltration of neutrophils macrophages, Th1 cells, elevation of serum creatinine levels, reduced renal tubular cell death, and induction of regulatory T cells (Tregs) in kidneys. Intriguingly, a distinct kidney population of CD11chiMHCIIhiCD80loCD86lo regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-b production. Further mechanistic studies demonstrated that MSC-derived inducible nitric oxide synthase played an essential role in the differentiation of DC precursors into regulatory DCs in a SOCS3-dependent manner. Taken together, our findings demonstrated, for the first time, critical regulatory properties of MSCs for induction of regulatory DCs from DC precursors in I/R injury. This study elucidates an immunoregulatory mechanism of MSCs and further lays a solid foundation for application of MSCs in acute kidney injury therapy.
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