Human umbilical cord‐derived mesenchymal stem cells elicit macrophages into an anti‐inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats

Insulin resistance, a major characteristic of type 2 diabetes (T2D), is closely associated with adipose tissue macrophages (ATMs) that induce chronic low‐grade inflammation. Recently, mesenchymal stem cells (MSCs) have been identified in alleviation of insulin resistance. However, the underlying mechanism still remains elusive. Thus, we aimed to investigate whether the effect of MSCs on insulin resistance was related to macrophages phenotypes in adipose tissues of T2D rats. In this study, human umbilical cord‐derived MSCs (UC‐MSCs) infusion produced significantly anti‐diabetic effects and promoted insulin sensitivity in T2D rats that were induced by a high‐fat diet combined with streptozotocin and directed ATMs into an alternatively activated phenotype (M2, anti‐inflammatory). In vitro, MSC‐induced M2 macrophages alleviated insulin resistance caused by classically activated macrophages (M1, pro‐inflammatory). Further analysis showed that M1 stimulated UC‐MSCs to increase expression of interleukin (IL)‐6, a molecule which upregulated IL4R expression, promoted phosphorylation of STAT6 in macrophages, and eventually polarized macrophages into M2 phenotype. Moreover, the UC‐MSCs effect on macrophages was largely abrogated by small interfering RNA (siRNA) knockdown of IL‐6. Together, our results indicate that UC‐MSCs can alleviate insulin resistance in part via production of IL‐6 that elicits M2 polarization. Additionally, human obesity and insulin resistance were associated with increased pro‐inflammatory ATMs infiltration. Thus, MSCs may be a new treatment for obesity‐related insulin resistance and T2D concerning macrophage polarized effects. Stem Cells 2016;34:627–639