Mesenchymal Stem Cells Polarize Macrophages to an Anti-Inflammatory Phenotype to Ameliorate Diabetic Nephropathy

In diabetic nephropathy (DN), classically activated macrophages (M1) are significantly increased, whereas alternatively activated macrophages (M2) are markedly decreased in the renal tissues. Mesenchymal stem cells (MSCs) have been shown to stimulate macrophages from M1 phenotype to M2 phenotype. Thus, we aimed to investigate whether the polarization of M1/M2 induced by MSCs was involved in DN. We injected human umbilical cord MSCs (UC-MSCs) into DN rats and found UC-MSC infusion reduced the infiltration of M1 macrophages and increased the infiltration of M2 macrophages in the glomerulus, thereby attenuating histopathological renal damage and improving renal inflammation and fibrosis in DN rats. Then, peritoneal macrophages were extracted and directed into M1 macrophages by lipopolysaccharides (LPS) in vitro. After coculturing UC-MSCs with M1 macrophages, we found that the M1 macrophage markers and related pro-inflammatory cytokines decreased. However, the expression of the M2 macrophage markers, as well as the anti-inflammatory cytokines, increased observably. Furthermore, UC-MSCs increased the expression of interleukin-4 receptor alpha chain (IL-4Rα) on macrophages by secreting interleukin-6 (IL-6); blocking IL-6 secretion inhibited the effect of UC-MSCs on M2 macrophage polarization. Then, we explored the mechanism by which M2 macrophages ameliorate DN in vitro and found that UC-MSC-induced M2 macrophages attenuated the secretion of the chemokine monocyte chemoattractant protein-1 (MCP-1) in hyperglycemia-induced mesangial cells, which led to reduced macrophage recruitment and infiltration. Moreover, UC-MSC-induced M2 macrophages inhibited transforming growth factor β (TGF-β) in glomerular mesangial cells. Our study proposes and discusses a mechanism by which MSCs promote the polarization of macrophages from M1 into M2 in the kidney, thereby ameliorating DN.