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

Yaqi Yin,Jieqing Gao,Jiejie Liu,Yu Cheng,Weidong Han,Jing Xue,Zongyan Xie,Qi Zhang,Li Zang,Haojie Hao,Yiming Mu

doi:10.1038/s41419-018-0801-9

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.

Highlights

Progressive pancreatic β-cell dysfunction and apoptosis are recognized as a fundamental pathology of type 2 diabetes (T2D)[1], and accumulated evidences suggest that part of the reason is the dramatically increased macrophages within T2D islets[2]
HUC-mesenchymal stem cells (MSCs) infusion improved glucose homeostasis and restored islets function in T2D mice The T2D mouse model was induced by a combination of 12-week high-fat diet (HFD) and a single introperitoneal injection of low-dose streptozotocin (STZ)
Macrophages are constitutively present within islets, where they provide a suitable microenvironment for β-cell development and the maintenance of islet homeostasis[33,34]

Summary

Introduction

Progressive pancreatic β-cell dysfunction and apoptosis are recognized as a fundamental pathology of type 2 diabetes (T2D)[1], and accumulated evidences suggest that part of the reason is the dramatically increased macrophages within T2D islets[2]. While alternatively activated M2-type macrophages, characterized by the expression of Fizz[1], CD206, and arginase-1 (Arg1), were reported to produce antiinflammatory cytokines and growth factors, contributing to inflammation suppression, wound healing and tissue regeneration. In islets of the T2D mice, the number of macrophages dramatically increased and macrophage polarity appeared to be shifted toward M1. These M1 macrophages tended to express high levels of pro-inflammatory cytokines, subsequently resulted in progressive β-cell dysfunction and loss

Methods

Results

Conclusion