Mitochondrial transfer from MSCs to macrophages restricts inflammation and alleviates kidney injury in diabetic nephropathy mice via PGC-1α activation.

Mesenchymal stem cells (MSCs) have fueled ample translation for treatment of immune-mediated diseases. Our previous study had demonstrated that MSCs could elicit macrophages (Mϕ) into anti-inflammatory phenotypes, and alleviate kidney injury in diabetic nephropathy mice via improving mitochondrial function of Mϕ, yet the specific mechanism was unclear. Recent evidence indicated that MSCs communicated with their microenvironment through exchanges of mitochondria. By a co-culture system consisting of MSCs and Mϕ, we showed that MSCs-derived mitochondria (MSCs-Mito) were transferred into Mϕ, and the mitochondrial functions were improved, which contributed to M2 polarization. Furthermore, we found that MSCs-Mito transfer activated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis. In addition, PGC-1α interacted with TFEB in high glucose (HG)-induced Mϕ, leading to the elevated lysosome-autophagy, which was essential to removal of damaged mitochondria. As a result, in Mϕ the mitochondrial bioenergy and capacity to combat inflammatory response were enhanced. Whereas, the immune-regulatory activity of MSCs-Mito was significantly blocked in PGC-1α knockdown Mϕ. More importantly, MSCs-Mito transfer could be observed in DN mice, and the adoptive transfer of MSCs-Mito educated Mϕ (MϕMito ) inhibited the inflammatory response and alleviated kidney injury. While the kidney-protective effects of MϕMito were abolished when the MSCs-Mito was impaired with rotenone (Rot), and the similar results were also observed when MϕMito were transfected with sipgc-1α before administration. Collectively, these findings suggested that MSCs elicited Mϕ into anti-inflammatory phenotype and ameliorated kidney injury through mitochondrial transfer in DN mice, and the effects were relied on PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated lysosome-autophagy. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Our previous study had demonstrated that MSCs elicited Mϕ into M2 phenotype via improving mitochondrial function of Mϕ, yet the specific mechanism remained to be elucidated. The current study was the first to assess the potential role of mitochondrial transfer from MSCs to Mϕ and further explore the underlying mechanisms. We found that mitochondrial transfer from MSCs to Mϕ restricted inflammation and alleviated kidney injury in diabetic nephropathy mice via PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated autophagy. While shedding light on this new immune-regulatory mechanism, our findings offer strategies to improve cell-based therapies or eventual cell-free therapeutic approaches for inflammation-related diseases.