Cellular and molecular basis of wound healing in diabetes

Abstract

Diabetic foot ulcers (DFUs), a leading cause of amputations, affect 15% of people with diabetes. A series of multiple mechanisms, including decreased cell and growth factor response, lead to diminished peripheral blood flow and decreased local angiogenesis, all of which can contribute to lack of healing in persons with DFUs. In this issue of the JCI, Gallagher and colleagues demonstrate that in diabetic mice, hyperoxia enhances the mobilization of circulating endothelial progenitor cells (EPCs) from the bone marrow to the peripheral circulation (see the related article beginning on page 1249). Local injection of the chemokine stromal cell-derived factor-1alpha then recruits these EPCs to the cutaneous wound site, resulting in accelerated wound healing. Thus, Gallagher et al. have identified novel potential targets for therapeutic intervention in diabetic wound healing.

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Figure 2. Molecular basis of debridement.

A typical foot ulcer in a person with diabetes is shown at top. (i) The nonhealing edge (callus) containing ulcerogenic cells with molecular markers indicative of healing impairment. (ii) Phenotypically normal but physiologically impaired cells, which can be stimulated to heal. Despite a wound’s appearance after debridement, it may not be healing and may need to be evaluated for the presence of molecular markers of inhibition and/or hyperkeratotic tissue (e.g., c-myc and β-catenin). We expect more such molecular markers will be identified in the future. Once a wound is debrided, pathology analyses along with immunohistochemistry should determine whether the extent of debridement was sufficient. If the extent of debridement was not sufficient (lower left diagram), cells positive for c-myc (green) and nuclear β-catenin (purple) will be found, indicating the presence of ulcerogenic cells, which will prevent the wound from healing and indicate that additional debridement is necessary. Lack of healing is also demarcated by a thicker epidermis, thicker cornified layer, and presence of nuclei in the cornified layer. If the debridement was successful (lower right lower diagram), no staining for c-myc or β-catenin will be found, indicating an absence of ulcerogenic cells and successful debridement. These markers of inhibition are useful, but the most important goal is actual healing as defined by the appearance of new epithelium, decreased area of the wound, and no drainage. This information should be stored electronically in the Wound Electronic Medical Record (WEMR), which provides an objective analysis coupled with pathology and microbiology reports.

Figure 1. Mechanisms of wound healing in healthy people versus people with diabetes.

In healthy individuals (left), the acute wound healing process is guided and maintained through integration of multiple signals (in the form of cytokines and chemokines) released by keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. During wound-induced hypoxia, VEGF released by macrophages, fibroblasts, and epithelial cells induces the phosphorylation and activation of eNOS in the bone marrow, resulting in an increase in NO levels, which triggers the mobilization of bone marrow EPCs to the circulation. The chemokine SDF-1α promotes the homing of these EPCs to the site of injury, where they participate in neovasculogenesis. In this issue of the JCI, Gallagher et al. (18) show that, in a murine model of diabetes (right), eNOS phosphorylation in the bone marrow is impaired, which directly limits EPC mobilization from the bone marrow into the circulation. They also show that SDF-1α expression is decreased in epithelial cells and myofibroblasts in the diabetic wound, which prevents EPC homing to wounds and therefore limits wound healing. The authors further show that establishing hyperoxia in wound tissue (via HBO therapy) activated many NOS isoforms, increased NO levels, and enhanced EPC mobilization to the circulation. However, local administration of SDF-1α was required to trigger homing of these cells to the wound site. These results suggest that HBO therapy combined with SDF-1α administration may be a potential therapeutic option to accelerate diabetic wound healing alone or in combination with existing clinical protocols.