Netrin-1 Improves The Effect Of Mesenchymal Stem Cells On Angiogenesis

BackgroundSimilar to the neural network, the vascular network is formed from central axial structures that send sprouts along predetermined trajectories to their distal destinations. Indeed, recent evidence indicates that neuronal guidance factors and their receptors function as angiogenic regulators. As neural guidance cues, netrin-1 is the most extensively studied gene in the field of angiogenesis. Despite achieving some advances in mesenchymal stem cell (MSC) therapy in angiogenesis, there are still a number of patients who fail to respond to cell therapy. Thus, a novel therapeutic strategy to enhance the angiogenic property of transplanted cells is desirable.ObjectiveThis study examined the impact of netrin-1 protein in combination with MSC implantation on therapeutic angiogenesis in a rat model of hind limb ischemia. Methods and resultsHind limb ischemic rats (n=24) were divided randomly into 4 groups (6 rats per group): control group (0.05 ml saline); netrin-1 group (1μg netrin-1 dissolved in 0.05 ml saline); MSC group (1×106 MSCs); and netrin-1/MSCs group (1μg netrin-1and 1×106 MSCs). Netrin-1 and/or MSCs were injected directly into the muscle of the ischemic limb. The gross appearance of the ischemic limb, collateral vessel formation, and the level of vascular endothelial growth factor (VEGF) were assessed 28 days after treatment. Netrin-1 protein in combination with MSCs transplantation markedly augmented the angiographic score and capillary density, improved ischemic limb function, and increased the levels of VEGF in the plasma and damaged tissues. Further studies assaying cell migration and network formation suggested that netrin-1 promoted MSC migration and enhanced its ability to participate in tube formation.ConclusionsTransplantation of MSCs in combination with netrin-1 protein significantly improved the therapeutic effect of MSCs, and therefore may provide a novel therapeutic approach for ischemic disease.