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

Abstract

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 highfat 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 obesityrelated insulin resistance and T2D concerning macrophage polarized effects. STEM CELLS

Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism

“…Studies involving MSC transplantation in mouse models of macrophage hyperactivity, such as sepsis and zymosan induced peritonitis, disease amelioration with concomitant macrophage reprogramming was observed3940. Similarly, MSC transplantation in a rat model of diabetes resulted in conversion of adipose tissue associated macrophages to a M2 phenotype alongside correction of other disease parameters18. In all the above models, MSCs possibly interacted with inflammatory macrophages which were predominant in the disease scenario.…”

“…Adoptive transfer of alternatively activated macrophages have conferred protection in inflammatory diseases such as Type I diabetes, indicating their decisive roles in reprogramming host inflammation16. Further, few very recent evidences indicate an increased recruitment of anti-inflammatory macrophages in in vivo models of MSC transplantation were regeneration and repair was noted1718. Macrophages exist in a spectrum of functional states and exaggerated anti-inflammatory (M2) or inflammatory (M1) macrophage functional states are associated with distinct pathologies.…”

Mesenchymal stem cell therapy in type 2 diabetes mellitus

“…Further analysis showed that M1-stimulated UC-MSCs increased expression of IL-6. IL-6 upregulated IL4R expression, promoted phosphorylation of STAT6 in macrophages, and ultimately reprogrammed macrophages into an M2 phenotype [67]. In addition, conditioned media from adipose tissue-derived MSCs reversed insulin resistance in insulin-resistant cell models, as evidenced by restored insulin and stimulated glucose uptake, via up-regulation of the GLUT4 gene and reductions in IL-6 and plasminogen activator inhibitor-1 (PAI-1) gene expression [68].…”

Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro

“…Therefore, huMSCs are ideal seed cells in tissue engineering 7 . Furthermore, numerous studies have explored huMSC treatments and the effect on various conditions, such as acute lung injury, diabetes with insulin resistance and Alzheimer’s disease 8–11 .…”