The role of adipose-derived stem cells-derived extracellular vesicles in the treatment of diabetic foot ulcer: Trends and prospects

Abstract

Diabetic foot ulcer(DFU) is one of the most severe chronic complications of type 2 diabetes mellitus, which is mainly caused by peripheral vascular occlusion with various degrees of infection. Treatment of DFU is difficult, and ulcer formation in lower limbs and deep-tissue necrosis might lead to disability or even death. Insulin resistance is the major mechanism of type 2 diabetes mellitus development, largely caused by adipose tissue dysfunction. However, adipose tissue was recently identified as an important endocrine organ that secretes bio-active factors, such as adipokines and extracellular vesicles(EVs). And adipose tissue-derived stem cells(ADSCs) are abundant in adipose tissue and have become a hot topic in the tissue engineering field. In particular, EVs derived from ADSCs contain abundant biomarkers and mediators. These EVs exert significant effects on distant cells and organs, contributing to metabolic homeostasis. In this review, we aim to elaborate on the mechanisms of diabetic non-healing wound development and the role of ADSCs-EVs in wound repair, which might provide a new therapy for treating DFU.

Keywords: adipose tissue-derived stem cells; diabetic foot ulcer; exosomes; extracellular vesicles; wound healing.

Figure 1

The mechanisms of diabetic non-healing wound development. Diabetic foot ulcers are caused by a number of factors that ultimately lead to chronic wound. These factors include persistent hyperglycaemia, diabetic neuropathy, peripheral artery disease, and local infection, which cause the impairment of angiogenesis and inflammatory cell function. Figure created using BioRender (https://biorender.com/).

Figure 2

The biogenesis and content of extracellular vesicles(EVs). There are 3 subtypes of EVs, including exosomes, microvesicles (MVs), and apoptotic bodies. Exosomes are generated from the fusion of multivesicular bodies (MVBs) with the plasma membrane, ranging from 40-160nm while MVs are directly produced from the outward budding of the plasma membrane with a diameter of 100-1000nm. Apoptotic bodies are released from the blebbing of dying cells and the diameter is about 100 to 5000 nm. EVs contain proteins, lipids, nucleic acids (DNA, mRNA, siRNA, microRNA, and long noncoding RNAs), and multi-molecular complexes. EVs, extracellular vesicles; MVs, microvesicles; MVBs, multivesicular bodies. Figure created using BioRender (https://biorender.com/).

Figure 3

The main mechanism of ADSCs-EVs on DFU in experimental models. ADSCs-EVs can reduce inflammatory cytokines, prevent cell senescence, increase capillary density, promote fibroblasts proliferation and collagen secretion via Wnt/β-catenin and PI3K/AKT signaling pathway to accelerate wound closure. ADSCs-EVs also can enhance the endothelial cells proliferation, migration, and tube formation through the PI3K-AKT-mTOR-HIF-1α axis to motivate angiogenesis. Under hypoxia conditions, ADSCs-EVs enhanced neovascularization partially through VEGF/VEGF-R pathway. ADSCs-EVs elevate the ratio of MMP3 to TIMP1 to remodel the extracellular matrix (ECM) and prevent fibroblasts differentiate into myofibroblasts in the early stage and cause excess collagen deposition in the late stage. ADSCs-EVs, adipose tissue-derived stem cells-derived extracellular vesicles; DFU, diabetic foot ulcer; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; HIF-1α, hypoxia-inducing factor alpha; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor; MMP3, matrix metalloproteinase 3; TIMP1, tissue inhibitor of matrix metalloproteinases-1; ECM, extracellular matrix. Figure created using BioRender (https://biorender.com/).