Stem Cells and Angiogenesis: Implications and Limitations in Enhancing Chronic Diabetic Foot Ulcer Healing

Abstract

Nonhealing diabetic foot ulcers (DFUs) are a continuing clinical issue despite the improved treatment with wound debridement, off-loading the ulcer, medication, wound dressings, and preventing infection by keeping the ulcer clean. Wound healing is associated with granulation tissue formation and angiogenesis favoring the wound to enter the resolution phase of healing followed by healing. However, chronic inflammation and reduced angiogenesis in a hyperglycemic environment impair the normal healing cascade and result in chronically non-healing diabetic foot ulcers. Promoting angiogenesis is associated with enhanced wound healing and using vascular endothelial growth factors has been proven beneficial to promote neo-angiogenesis. However, still, nonhealing DFUs persist with increased risks of amputation. Regenerative medicine is an evolving branch applicable in wound healing with the use of stem cells to promote angiogenesis. Various studies have reported promising results, but the associated limitations need in-depth research. This article focuses on summarizing and critically reviewing the published literature since 2021 on the use of stem cells to promote angiogenesis and enhance wound healing in chronic non-healing DFUs.

Extracellular vesicles derived from fibroblasts induced with or without high glucose exert opposite effects on wound healing and angiogenesis

“…As the medium of substance exchange, blood vessels play a vital role in the process of wound repair. Therefore, promotion of angiogenesis is necessary for early restoration of blood supply in injured tissues ( 16 ). The process of angiogenesis is well-orchestrated and regulated by many kinds of cytokines, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF-β1), hypoxia inducible factor (HIF-1α), and so on.…”

Function and mechanism of mesenchymal stem cells in the healing of diabetic foot wounds

“…Following previous studies in humans and animals, MSCs have achieved encouraging efficacy in treating DFU ( 241 , 254 , 257 ). However, with an increase in research, from the results of recent clinical studies, common side effects of MSCs in DFU are diarrhea, fever, increased serum creatinine level, urticaria, nausea, and vomiting ( 258 , 259 ). After the passage of stem cells for many times in vitro , the multidirectional differentiation potential and paracrine ability may also be reduced, leading to the decline of clinical effect ( 234 ).…”

Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing

“…Other means of improving resolvin stability may be in better transport systems. Exosomes or microvesicles have been proposed as transporting systems for drug delivery in the treatment of DFUs[ 37 ]. However, below the adequate levels of circulating Rv, bioavailability, and stability are common limitations and issues while using Rv and biopolymers[ 35 , 38 ].…”

“…Exosomes may have beneficial effects in disease states and have therapeutic implications in various diseases including the role in DFU wound healing[ 37 , 41 - 43 ]. Because of the ability of exosomes to modulate complex intercellular pathways, exosomes are thought to have therapeutic utility in treating many diseases.…”

“…This suggests that deficiencies in endogenous production and transportation of anti-inflammatory factors can be addressed by supplementing such factors through the application of anti-inflammatory-loaded exosomes (Table 2 ). The tissue and cell sources of the exosomes appear to play a role in their morphology, stability, and immunomodulatory ability[ 37 ] and thus, these aspects should be considered while modifying or pretreating exosomes to enhance their efficacy, stability, and bioavailability.…”