The role of keratinocyte function on the defected diabetic wound healing

Abstract

Non-healing wounds are a major complication of diabetes that can lead to limb amputation and disability in patients. The normal process of wound repair progresses through well-defined stages including hemostasis, inflammation, proliferative, and remodeling, which may be impaired in diabetic wounds. In recent years, it has been reported that keratinocytes, a major cell type in human skin, play a key role in the healing process of wounds. In this overview, firstly, a summary of the wound healing process is provided and the role of keratinocytes in wound healing is briefly reviewed. Then, a set of evidence about the impaired keratinocytes activities in diabetic wounds and clinical trials focused mainly on improving keratinocytes in the context of diabetic wound therapeutics are summarized. Keratinocytes can produce signaling molecules that act in a paracrine and autocrine way, causing pleiotropic effects on various cell types. The affected cells respond to keratinocytes by creating several signaling molecules, which also adjust keratinocyte activation through wound healing. In diabetic wounds, disruption of various biological mechanisms leads to dysfunction of keratinocytes including impaired migration, adhesion, and proliferation. The function of abnormal keratinocytes can lead to poor diabetic wound healing. Taken together, clarification of molecular and functional disturbances of keratinocyte cells and applying them in diabetic wounds can contribute to enhanced treatment of diabetic wounds. Based on the location of keratinocytes in the epidermis and the central role of keratinocytes in the diabetic wound healing process, applying keratinocytes has great potential for the treatment of diabetic burn wounds.

Keywords: Diabetic wound healing; diabetes; inflammation; keratinocytes.

Figure 1

Schematic diagram indicating the model of wound healing processes in normal condition compared to the diabetic wound.

Figure 2

The healing process in normal and diabetic wounds. (A) Events in normal wound healing process include: platelet aggregation (hemostasis phase); release of pro-inflammatory cytokines by neutrophils, macrophages, and mast cells (inflammation phase); healing response is initiated by decreasing inflammation, increasing angiogenesis, migration of fibroblasts and keratinocytes, and formation of ECM (remodeling phase) (B) Healing process in diabetic wounds is affected with a decrease in fibrinolysis and an imbalance of released cytokines, a decrease in angiogenesis, impaired proliferation and migration of keratinocytes, which resulted in delayed re-epithelialization in wounds, impaired collagen deposition and the poor synthesis of collagen and the ECM contributes to deficient wound closure (Figure adapted from Hesketh and others [18].

Figure 3

Macroscopic evaluation of wound in diabetic rat models. The day when the wounds were created was designated as 1^th day. On 3^rd, 7^th, 10^th and 14^th days after treatment, wound areas were measured. The four treatment groups include control (Non-treated diabetic rats), KT (keratinocytes-treated groups), LP (PRP-treated groups), LP + KT (Local PRP + keratinocytes-treated groups). Figure adapted from Mansoub and others [64].

Figure 4

Treatment of a diabetic foot ulcer using an allogeneic keratinocyte product. A 63 years old woman with a chronic diabetic wound on the right fifth toe. (A) Cultured allogeneic keratinocyte sheet. (B-E) The ulcer was completely healed after 3 weeks of treatment. (Figure adapted from You and Han [70]).