Author: Gurjot Singh
Institution: Bangalore Medical College
Date: May 2007
Impaired wound healing is a major clinical problem in diabetic patients, affecting about 15 percent of them and is the leading cause of lower limb amputations. Reporting in the May issue of The Journal of Clinical Investigation, researchers at the University of Pennsylvania Medical Center have, for the first time, identified the molecular basis of impaired vasculogenesis in diabetic wound healing. By fixing the defective links in the process, they were able to significantly enhance wound healing, thus providing novel potential targets for therapeutic intervention in diabetic wound healing. The current therapies for this impairment are few and inadequate.
One of the cardinal features of wound healing is the formation of new small blood vessels at the site of injury. One of the ways in which this happens is by bone marrow-derived progenitor cells called Endothelial Progenitor Cells (EPCs), in a process known as vasculogenesis. Poor healing of diabetic wound is characterized by impaired vasculogenesis. The process by which EPCs lead to the formation of new blood vessels involves two important links,the mobilization of EPCs from bone marrow into circulation and the recruitment of EPCs from the circulation to the repair site. The cascade begins when a vessel growth-promoting factor called VEGF (Vasoactive Endothelial Growth Factor) is released by ischemic tissue, like a diabetic wound complicated by decreased blood flow. VEGF goes to the bone marrow and activates an enzyme called nitric oxide synthase (NOS) which, as the name suggests, produces a diffusible chemical called nitric oxide or NO. This increased NO leads to the mobilization of EPCs from the bone marrow into the circulation. Once in the circulation, they need to migrate to the site of repair. This is dependent on the increased levels of a chemical called SDF-1α which "attracts" the EPCs to the workplace (see Fig 1). At the wound site, they begin the process of neovascularization (i.e., formation of new blood vessels) and healing. Now what goes wrong with chain of events in diabetes was unknown, that is, until recently.
Katherine Gallagher and colleagues have found that both these links-EPC mobilization and recruitment-are defective in diabetic mice as compared to healthy ones. Further, mending these defects by specific therapeutic interventions led to marked improvement in wound healing.
Working on the first step, the researchers showed that the levels of the enzyme NOS, which is needed for NO production and EPC mobilization, are reduced in the bone marrow of diabetic mice as compared to healthy ones (see Fig 1). This led to a reduction, by as much as 50 percent, in the number of circulating EPCs. They then tested the effect of hyperoxia (excessive oxygen in the system due to exposure to high pressure oxygen) which has been shown to stimulate NOS in some tissues on the diabetic mice. And sure enough, hyperoxia led to a marked increase in the bone marrow-NO levels and a consequent fivefold increase in the number of circulating EPCs (when NOS was inhibited before hyperoxia administration, no increase in EPC mobilization was observed, thus underscoring the importance of this enzyme in this pathway). However, even when the number of circulating EPCs was increased, there was no significant change in the number of EPCs reaching the wound site. This is where the second part of the story comes in.
After being mobilized into the circulation, EPCs need to be called to the site of action, which is done by increased levels of the chemical SDF-1α. Gallagher and colleagues found that in diabetic mice, SDF-1α levels were reduced by as much as 50 percent (see Fig 1). Predictably, injection of SDF-1α into the wound led to an increase in the number of wound EPCs.
Even better, when both hyperoxia and SDF-1a were given together, a synergistic effect was produced, thus supporting the conclusion that mobilization of EPCs into the circulation along with their recruitment to the wound site lead to improved wound healing in diabetics (see fig 2).
This study opens exciting new vistas for both further basic research and therapeutic innovations. In the past too, hyperoxia based therapies have been used for diabetic patients, but they have provided inconsistent results. That may be due to the fact that such interventions target only one leg of the EPC response, the mobilization. Gallagher and colleagues demonstrate that the recruitment of EPCs is integral to EPC-mediated healing and targeting just one aspect of the latter would be inadequate. "Therefore, future therapies for ischemic complications will have to be based on correcting multiple deficits simultaneously. Therapeutic interventions, including correcting both EPC activation via hyperoxia and EPC homing via administration of SDF-1α may significantly accelerate diabetic wound healing by correcting the EPC deficit inherent to diabetic wounds," write Harold Brem and Marjana Tomic-Canic in an accompanying commentary to the article.
By Gurjot Singh.