Targeting epigenetic mechanisms in diabetic wound healing

Abstract

Impaired wound healing is a major secondary complication of type 2 diabetes that often results in limb loss and disability. Normal tissue repair progresses through discrete phases including hemostasis, inflammation, proliferation, and remodeling. In diabetes, normal progression through these phases is impaired resulting in a sustained inflammatory state and dysfunctional epithelialization in the wound. Due to their plasticity, macrophages play a critical role in the transition from the inflammation phase to the proliferation phase. Diabetes disrupts macrophage function by impairing monocyte recruitment to the wound, reducing phagocytosis, and prohibiting the transition of inflammatory macrophages to an anti-inflammatory state. Diabetes also impedes keratinocyte and fibroblast function during the later phases resulting in impaired epithelialization of the wound. Several recent studies suggest that altered epigenetic regulation of both immune and structural cells in wounds may influence cell phenotypes and healing, particularly in pathologic states, such as diabetes. Specifically, it has been shown that macrophage plasticity during wound repair is partly regulated epigenetically and that diabetes alters this epigenetic regulation and contributes to a sustained inflammatory state. Epigenetic regulation is also known to regulate keratinocyte and fibroblast function during wound repair. In this review, we provide an introduction to the epigenetic mechanisms that regulate tissue repair and highlight recent findings that demonstrate how epigenetic events are altered during the course of diabetic wound healing.

The Potential Role of Cycloastragenol in Promoting Diabetic Wound Repair In Vitro

“…Skin acts as a barrier to foreign pathogens, regulates body temperature, provides sensation, and prevents dehydration of the body [19]. With types of injury in which the skin is torn, cut, or punctured, a well-orchestrated repair process of hemostasis, inflammation, proliferation, and remodeling occurs [2,20]. Studies show these overlapping but distinct phases involve various inflammatory cells, repair cells and mediators, and cellular responses; the disruption of the cellular and molecular signals in conditions such as diabetes, infection, or radiation exposure may result in inefficient healing [20].…”

“…With types of injury in which the skin is torn, cut, or punctured, a well-orchestrated repair process of hemostasis, inflammation, proliferation, and remodeling occurs [2,20]. Studies show these overlapping but distinct phases involve various inflammatory cells, repair cells and mediators, and cellular responses; the disruption of the cellular and molecular signals in conditions such as diabetes, infection, or radiation exposure may result in inefficient healing [20]. Research has found that loss of resident EpSCs, impairment of migration capacity, and/or excessive differentiation of EpSCs are significantly associated with diabetic wound repair.…”

Tissue-Specific Role of Macrophages in Noninfectious Inflammatory Disorders

“…This change entails a deviation of the processes involved in the phased differentiation of macrophages in chronic wounds. Furthermore, if a large number of pro-inflammatory M1 macrophages persist in the wound, a long-term macrophage-mediated inflammatory response occurs [ 116 , 123 , 124 , 125 , 126 ].…”

“…One of the explanations for the chronicity of wounds in individuals with obesity and diabetes mellitus is the dysregulation of the recruitment and persistence and activation of monocytes/macrophages, as well as impaired efferocytosis processes. In the early stages of the repair of diabetic wounds, macrophage infiltration is delayed due to a decrease in CCL2 expression [ 126 , 127 , 128 ]. However, in the late stages of chronic wound healing, a large number of neutrophils and monocytes/macrophages persist in the injured site, along with an increase in the infiltration of MoMFs with the “classic” Ly6CHi phenotype during this period, which is not typical under normal conditions [ 128 , 129 , 130 ].…”

“…However, in the late stages of chronic wound healing, a large number of neutrophils and monocytes/macrophages persist in the injured site, along with an increase in the infiltration of MoMFs with the “classic” Ly6CHi phenotype during this period, which is not typical under normal conditions [ 128 , 129 , 130 ]. This effect is associated with high levels of gene expression and subsequent secretion of the key pro-inflammatory cytokines IL-1β and TNF-α and the chemokines MIP-2 and CCL2 during the late stages of the wound healing process [ 126 , 129 ].…”