Human umbilical cord-derived mesenchymal stem cells direct macrophage polarization to alleviate pancreatic islets dysfunction in type 2 diabetic mice

Abstract

Progressive pancreatic β-cell dysfunction is recognized as a fundamental pathology of type 2 diabetes (T2D). Recently, mesenchymal stem cells (MSCs) have been identified in protection of islets function in T2D individuals. However, the underlying mechanisms remain elusive. It is widely accepted that β-cell dysfunction is closely related to improper accumulation of macrophages in the islets, and a series of reports suggest that MSCs possess great immunomodulatory properties by which they could elicit macrophages into an anti-inflammatory M2 state. In this study, we induced a T2D mouse model with a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ), and then performed human umbilical cord-derived MSCs (hUC-MSCs) infusion to investigate whether the effect of MSCs on islets protection was related to regulation on macrophages in pancreatic islets. hUC-MSCs infusion exerted anti-diabetic effects and significantly promoted islets recovery in T2D mice. Interestingly, pancreatic inflammation was remarkably suppressed, and local M1 macrophages were directed toward an anti-inflammatory M2-like state after hUC-MSC infusion. In vitro study also proved that hUC-MSCs inhibited the activation of the M1 phenotype and induced the generation of the M2 phenotype in isolated mouse bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs) and in THP-1 cells. Further analysis showed that M1-stimulated hUC-MSCs increased the secretion of interleukin (IL)-6, blocking which by small interfering RNA (siRNA) largely abrogated the hUC-MSCs effects on macrophages both in vitro and in vivo, resulting in dampened restoration of β-cell function and glucose homeostasis in T2D mice. In addition, MCP-1 was found to work in accordance with IL-6 in directing macrophage polarization from M1 to M2 state. These data may provide new clues for searching for the target of β-cell protection. Furthermore, hUC-MSCs may be a superior alternative in treating T2D for their macrophage polarization effects.

Mesenchymal stem cells elicit macrophages into M2 phenotype via improving transcription factor EB-mediated autophagy to alleviate diabetic nephropathy

“…Taken together, these studies have demonstrated that the deficient autophagy in macrophages was correlated to systemic inflammation in type 1 and 2 diabetic mice. Additionally, several studies have shown that MSCs treatment elicited macrophages into M2 phenotype in type 2 diabetic models . In the present study, we confirmed that MSCs treatment improved mitochondrial bioenergetics, activated autophagy and elicited M2 Mφ polarization in DN mice, whereas the beneficial effect was blunted when autophagy was blocked with HCQ, indicating that immune‐regulation of MSCs is dependent on autophagy.…”

Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation

“…IL-1Ra can also regulate the phenotype switch of macrophages [49]. A previous study in T2DM mice has shown that MSCs infusion improved the b cell function through promoting the phenotype switch of macrophages in the diabetic mice islets [50]. Therefore it is possible that macrophages may also be involved in restoring the homeostasis of human T2DM islets.…”

Suppression of TLR4 by miR-448 is involved in Diabetic development via regulating Macrophage polarization

“…Mice were then randomly assigned into two groups ( n = 8 per group), type 2 diabetes (T2D) and negative control group. The mice in T2D group were generated by a combination administration of streptozotocin (STZ) and a high‐fat diet (HFD) according to the previous reports . After 4 h fasting, T2D group mice received an intraperitoneal injection of STZ (Sigma‐Aldrich, St Louis, MO, USA) in citrate buffer (120 mg/kg body weight).…”

“…The mice in T2D group were generated by a combination administration of streptozotocin (STZ) and a highfat diet (HFD) according to the previous reports. [21,22] After 4 h fasting, T2D group mice received an intraperitoneal injection of STZ (Sigma-Aldrich, St Louis, MO, USA) in citrate buffer (120 mg/kg body weight). After 3 weeks of STZ injection, T2D group mice were given HFD (21.8 kJ/g) for 7 weeks.…”