1492 Prostacyclin pathway to enhance wound healing in diabetic foot ulcers

Prostacyclin or pgi2 signaling pathway was found defective in diabetic foot ulcers (DFUs) and reflected its healing potential when supplemented to DFU patients. To decipher the healing activity of pgi2 in the case of DFUs, we are assessing the effect of treprostinil, a pgi2 analog, on cell migration, angiogenesis, and remodeling phases using 2D cell culture-based and 3D prevascularized wounded DFU skin-like models. First, we have generated well-differentiated and prevascularized 3D fibrin-based skin constructs using healthy and primary adult-derived keratinocytes and fibroblasts. At the 2D level, fibroblasts extracted from DFU patients' amputated toes were tested for their migratory activity in presence of treprostinil with and without pgi2 receptor-IP blocker using scratch wound assays. Results indicated that treprostinil was significantly delaying fibroblast migration derived from healthy donors in a concentration-dependent manner specifically when applied in 10-5 (p<0.001),10-6 (p=0.005), and 10-7M (p<0.001). This delay was mediated through the IP receptor at treprostinil10-7M when using IP-blocker at 10-6M (p=0.007). On DFU-derived cells, treprostinil didn’t report any significant effect on fibroblast migration. Our results were the first to explore the pgi2 migratory impact on DFU-derived fibroblasts which makes our findings interesting to detect the defect that renders diabetic fibroblasts irresponsive to Pgi2. Also, continued explorations of treprostinil migratory and angiogenic effects on DFU-derived keratinocytes and dermal microvascular endothelial cells respectively, at 2D and 3D levels are promising to generate a complete picture of the pgi2 role in restoring the impaired healing activity in DFUs.