Diabetic ulcers are chronic cutaneous complications that amount to more than $50M in healthcare costs and are the leading cause of lower extremity amputations. In part, diabetic wound repair pathology results from over-production of reactive oxygen species (ROS) that stem from mis-regulation of Nrf2, a master transcriptional regulator of antioxidant genes. While regulation of Nrf2 and redox balance is critical for proper wound repair, the precise role of Nrf2 in coordinating wound regeneration is unclear. Here, utilizing an in-depth analysis of Nrf2 in the wound environment, we uncover an indispensable role of epithelial Nrf2 in promoting adult cutaneous re-epithelialization. Through spatio-temporal expression analysis and chromatin immunoprecipitation, we show mis-regulation of Nrf2 in diabetic wounds results from defective nuclear translocation of Nrf2 in epithelial cells of the wound environment (WT 96.97±3.58% vs. Diabetic 22.5±16.40%). Integrating K14-CreER;Nrf2flox/flox double transgenic mice, we demonstrate epithelial-specific deletion of Nrf2 results in a significant wound healing delay that is reminiscent to the diabetic wound burden (Control 16±0 days vs. Diabetic 32±0 days vs. KO 33±2 days). In addition to compromised proliferation indicated by reduced expression of Ki67+ in the epidermis (Control 66.36±7.63% vs. KO 25.78±4.01% p=0.0004), Nrf2-null keratinocytes exhibit reduced capacity to migrate in explant cultures. Using high-throughput transcriptome analysis and ex vivo functional assays, we show a prominent role of Nrf2 in regulating epidermal migration by governing directly governing onset of epithelial-to-mesenchymal transition (EMT) by regulating expression of Snai1 and Twist1 (5.6 and 8.9-fold reduction, respectably), two important regulators of EMT. Together, we provide evidence demonstrating the importance of Nrf2 in regulating critical events underlying wound repair and highlight its value as a promising agent in therapeutic intervention.


A.P. Villarreal Ponce: None. J.A. David: None. M. Worku Tiruneh: None. S. Abdou: None. D. Sultan: None. J. Kwong: None. J. Kuhn: None. P.S. Rabbani: None. D. Ceradini: None.


American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-08 to D.C.)

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