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Mesenchymal Stem Cells Elicit Macrophages into M2 Phenotype via Improving TFEB‐mediated Autophagy to Alleviate Diabetic Nephropathy

Diabetic nephropathy (DN) is a leading cause of end‐stage renal disease. Chronic inflammation is recognized as a key causal factor in the development and progression of DN, and the imbalance of M1/M2 macrophages (Mϕ) contributes to this process. Mesenchymal stem cells (MSCs) have been reported to prevent renal injuries via immune regulation in diabetic models, but whether these benefits are owing to the regulation of Mϕ, and the underlying signaling pathways are unknown. Here, we showed that MSCs elicited Mϕ into M2 phenotype and prevented renal injuries in DN mice, but these effects were abolished when the Mϕ were depleted by clodronate liposomes (Lipo‐Clod), suggesting that Mϕ were necessary for renal protection of MSCs in DN mice. Moreover, the MSCs promoted M2 polarization was attributable to the activation of TFEB and subsequent restore of lysosomal function and autophagy activity in Mϕ. Furthermore, in vivo adoptive transfer of Mϕin vivo (Mϕ from DN+MSCs mice) or MϕMSCs (Mϕ co‐cultured with MSCs in vitro) to DN mice improved renal function. While, TFEB knockdown in Mϕ significantly abolished the protective role of MϕMSCs. Altogether, these findings revealed that MSCs suppress inflammatory response and alleviate renal injuries in DN mice via TFEB dependent Mϕ switch.