Umbilical cord-matrix stem cells induce the functional restoration of vascular endothelial cells and enhance skin wound healing in diabetic mice via the polarized macrophages

Shichang Zhang,Guoying Zhang,Bo Zhang,Li Chen

doi:10.1186/s13287-020-1561-x

Abstract

BackgroundChronic nonhealing wounds represent one of the most common complications of diabetes and require advanced treatment strategies. Increasing evidence supports the important role of mesenchymal stem cells in diabetic wound healing; however, the underlying mechanism remains unclear. Here, we explored the effects of umbilical cord-matrix stem cells (UCMSCs) on diabetic wound healing and the underlying mechanism.MethodsUCMSCs or conditioned medium (UCMSC-CM) were injected into the cutaneous wounds of streptozotocin-induced diabetic mice. The effects of this treatment on macrophages and diabetic vascular endothelial cells were investigated in vivo and in vitro.ResultsOur results reveal that UCMSCs or UCMSC-CM accelerated wound healing by enhancing angiogenesis. The number of host macrophages recruited to the wound tissue by local infusion of UCMSCs was greater than that recruited by fibroblast transplantation or control. The frequency of M2 macrophages was increased by UCMSC transplantation or UCMSC-CM injection, which promoted the expression of cytokines derived from M2 macrophages. Furthermore, when cocultured with UCMSCs or UCMSC-CM, lipopolysaccharide-induced macrophages acquired an anti-inflammatory M2 phenotype characterized by the increased secretion of the cytokines interleukin (IL)-10 and vascular endothelial growth factor and the suppressed production of tumor necrosis factor-α and IL-6. UCMSC-CM-activated macrophages significantly enhanced diabetic vascular endothelial cell functions, including angiogenesis, migration, and chemotaxis. Moreover, the action of UCMSC-CM on macrophages or vascular endothelial cells was abrogated by the administration of neutralizing antibodies against prostaglandin E2 (PGE2) or by the inhibition of PGE2 secretion from UCMSCs.ConclusionsOur findings demonstrate that UCMSCs can induce the functional restoration of vascular endothelial cells via the remodeling of macrophage phenotypes, which might contribute to the marked acceleration of wound healing in diabetic mice.Graphical

Highlights

Chronic wounds, such as diabetic ulcers, are a major clinical problem in diabetic patients and can lead to severe outcomes, including increased amputation rates and even death [1]
Our findings demonstrate that umbilical cordmatrix stem cell (UCMSC) can induce the functional restoration of vascular endothelial cells via the remodeling of macrophage phenotypes, which might contribute to the marked acceleration of wound healing in diabetic mice
The area under curve analysis revealed that the overall rate of wound healing was significantly greater in mice that received UCMSCs or UCMSC-Conditioned medium (CM) starting from day 0 to day 14 than in mice that received FB or PBS administration (Fig. 1b)

Summary

Introduction

Chronic wounds, such as diabetic ulcers, are a major clinical problem in diabetic patients and can lead to severe outcomes, including increased amputation rates and even death [1]. There is growing evidence suggesting that mesenchymal stem cell (MSC)-based therapies can promote diabetic wound healing via enhanced angiogenesis, which obviates the distress of nonhealing and amputation [2,3,4,5]. The therapeutic potential of autologous stem cells is impaired by the severe reduction in number and dysfunction of MSCs derived from diabetic patients with long-term disease [7, 8]. Increasing evidence supports the important role of mesenchymal stem cells in diabetic wound healing; the underlying mechanism remains unclear. We explored the effects of umbilical cord-matrix stem cells (UCMSCs) on diabetic wound healing and the underlying mechanism

Methods

Results

Discussion

Conclusion