Chronic wounds constitute a type of age-related disease, and one of its leading causes is diabetic mellitus (DM)(1). Currently, the standard treatments for diabetic wounds are debridement, negative pressure aspiration, and skin grafting(2, 3). However, due to the characteristics of diabetic wounds, such as an abnormal inflammatory response, decreased angiogenesis, and disturbance of the microenvironment of the wound surface, these treatments have achieved limited benefits(4). As wound healing is a heavy burden for patients both physically and financially, how to rebalance microenvironments and provide better conditions for wound healing remain major challenges in clinical treatment(1).
In general, the wound healing process can be divided into several stages: immediate hemostasis, acute inflammation, proliferation, and maturation(5). In normal wounds, injured tissue proliferates rapidly in granulation tissue, characterized by intense angiogenesis(6). The most important feature of diabetic wounds is the decrease in the number of new blood vessels in the wound, resulting in insufficient blood supply to the wound, which in turn affects cell proliferation and tissue restructuring(7). One of the purposes of clinical treatment is to provide a sufficient blood supply to the wound to promote the proliferation of wound cells and the survival of skin grafting(8, 9). Therefore, how to further improve the number of blood vessels on the wound is important to the healing of diabetic ulcers.
Stem cell-based therapy is considered a promising approach for treating diabetic wounds because stem cells are pluripotent, can self-renew and have the ability to regulate their microenvironment(10). Our previous study found that epidermal basal cell suspensions, which contain epidermal stem cells (EpiSCs), can promote wound healing in patients with or without diabetes(11, 12). Additional studies found that EpiSCs can proliferate in the wound area and accelerate wound healing in SD rats and DB/DB mice(13, 14). EpiSCs have the ability to promote angiogenesis and regulate inflammation in chronic wounds(13). However, how EpiSCs affect these biological processes and promote wound healing remains unknown.
Exosomes, with a diameter of approximately 100 nm, are among of the components secreted by almost every cell(15). The uptake and release of exosomes is an important means to communicate information between cells over long distances(16). Studies have found that exosomes from different kinds of stem cells can regulate wound healing(17–19). The role of exosomes in the diagnosis and treatment of clinical diseases has been gradually revealed(20). It is believed that these extracellular vesicles, which are rich in proteins, lipids and nucleic acids, are the main contributors to stem cell efficacy.
MicroRNAs (miRNAs), which are short (19- to 25-nt) RNAs, are one of the main substances that are abundant in exosomes(21). MicroRNAs target the 3′ untranslated region of mRNAs, forming a transient double-stranded miRNA duplex, and then the mature miRNA strand is incorporated into the RNA-induced silencing complex to mediate gene silencing and passenger strand degradation(22). A single miRNA can target hundreds of mRNAs and influence the expression of many genes(23). Moreover, miRNAs delivered by exosomes function as posttranscriptional regulators by forming silencing complexes that further affect biological processes within cells(24).
Apoptosis and autophagy are important intracellular processes that maintain organism homeostasis and promote survival(25). Autophagy involves the selective degradation of damaged cellular organelles and protein aggregates, while apoptosis involves the removal of damaged or aged cells(26, 27). Apoptosis and autophagy are in a state of dynamic equilibrium within the cell(28). Autophagy is induced when there is proper external stimulation, thereby coping with organelle damage, such as endoplasmic reticulum stress, to promote cell survival(29). Excessive external stimulation unsuitable for cell survival, such as a high-glucose environment, can lead to the induction of excessive autophagy, which further leads to autophagy-induced apoptosis(30–32). In our study, we found that excessive autophagy is the reason for endothelial cell apoptosis under high-glucose conditions. Therefore, the inhibition of excessive autophagy within cells under extreme conditions promotes cell survival and further benefits the healing process of diabetic wounds.
In our study, we found that miR200b-3p delivered by epidermal stem cell-derived exosomes (EpiSC-EXOs) downregulated high glucose-induced endothelial cell apoptosis, which further explained the effectiveness of EpiSCs in diabetic wound healing.