Umbilical cord mesenchymal stem cell-derived apoptotic extracellular vesicles ameliorate cutaneous wound healing in type 2 diabetic mice via macrophage pyroptosis inhibition

Abstract

Background: Delayed healing of diabetic cutaneous wounds is one of the most common complications of type 2 diabetes mellitus (T2DM), which can bring great distress to patients. In diabetic patients, macrophages accumulate around skin wounds and produce NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasomes, which in turn undergo pyroptosis and produce inflammatory factors such as interleukin-1β that affect wound healing. Although our previous study revealed that apoptotic extracellular vesicles (ApoEVs) produced from mesenchymal stem cells (MSCs) improve cutaneous wound healing in normal C57BL/6 mice, whether ApoEVs can also improve diabetic wound healing remains unclear. Methods: Umbilical cord mesenchymal stem cells (UCMSCs) were cultured in vitro and apoptosis was induced. ApoEVs were extracted and identified and used in a T2DM mouse cutaneous wound model to evaluate the efficacy. The inhibitory effect of ApoEVs on macrophage pyroptosis was verified in vivo and in vitro, and the level of oxidative stress in macrophages was assessed to explore the mechanism by which ApoEVs play a role. Results: UCMSC-derived ApoEVs improved skin defect healing in T2DM mice. Moreover, UCMSC-derived ApoEVs inhibited macrophage pyroptosis in T2DM mice in vivo as well as in vitro under high glucose culture conditions. In addition, we demonstrated that ApoEVs reduce oxidative stress levels, which is a possible mechanism by which they inhibit macrophage pyroptosis. Conclusions:Our study confirmed that local application of UCMSC-derived ApoEVs improved cutaneous wound healing in T2DM mice. ApoEVs, as products of MSC apoptosis, can inhibit macrophage pyroptosis and regulate the death process by decreasing the level of oxidative stress.

The Mechanism of Pyroptosis and Its Application Prospect in Diabetic Wound Healing

“… 205–208 A study by Wang et al demonstrated that ApoEVs derived from UCMSCs improved wound healing in db/db mice by suppressing the level of pyroptosis-associated proteins such as NLRP3, cleaved caspase-1, GSDMD, IL-1 and IL-18. 144 The authors showed that NLRP3, Caspase-1, GSDMD and F4/80 co-localized in pyroptotic BMDMs and ApoEV treatment significantly reduced the number of positive cells and fluorescence intensity in LPS/ATP-induced macrophages. Research investigations have shown that higher blood sugar levels may result in macrophage oxidative stress through the generation of excessive ROS in oxidative phosphorylation.…”

“… 215 ApoEVs derived from UCMSCs have been shown to effectively inhibit the accumulation of ROS, mitigate the generation of OS in macrophages and alleviate the occurrence of pyroptosis. 144 It has been demonstrated that the administration of ApoEVs is effective in modulating different types of cell death in a variety of cell types. Therefore, UCMSCs may provide a novel therapy for treating T2D-mediated wound healing and extend our understanding of the regulation of cell death.…”