Plastic Surgery Research Council
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KEAP1 SILENCING IMPROVES DIABETES-SPECIFIC DEFECTS IN MESENCHYMAL STEM CELL FUNCTION
Presenter: Yee Cheng Low, MD
Co-Authors: Low YC; Ham MJ; Lotfi P; Wilson SC; Lalezarzadeh F; Ojo CO; Saadeh PB; Ceradini DJ
NYU Medical Center

Background: Diabetes impairs tissue regeneration through pathologic accumulation of reactive oxygen species (ROS). As mesenchymal stem cells (MSCs) are critical to regenerative niche function, we postulated that the chronic oxidative stress of diabetes impairs both the MSC and its niche. We further hypothesized that activation of endogenous ROS scavenging pathways through increased NRF2-signaling, a central antioxidant program, can restore redox homeostasis and normalize diabetic regeneration.

Methods: MSCs isolated from age-matched diabetic and wildtype mice were assayed for ROS and redox-related gene expression. siRNA-mediated inhibition of the native NRF2 repressor, Keap1 (siKeap1), was used to activate the endogenous antioxidant cellular program. Functionally, we assayed the role of chronic hyperglycemic stress on MSC proliferation, migratory capacity, and differentiation potential. In a preclinical model of diabetic wound healing, we delivered topical Keap1 siRNA into the dermal regenerative niche.

Results: Chronic hyperglycemia impaired NRF2 nuclear translocation by 58% and intracellular ROS scavenging compared to control (decreased MnSOD & NQO1 expression by 60% & 39%, respectively, p<0.01 for all). Functionally, diabetic MSCs proliferated less (<50%), were more adipogenic, less osteogenic, and migrated towards SDF1a by < 50% compared to control (p<0.05 for all). Despite ongoing hyperglycemia, siKeap1 treatment restored NRF2-signaling within diabetic MSCs and normalized ROS to control levels. Furthermore, siKeap1 improved diabetic MSC proliferation to 85% of wildtype, normalized MSC differentiation, and enhanced migration towards SDF1a by 430% percent (p<0.05 for all measurements). Topical siKeap1 therapy accelerated wound closure by 7 days (p<0.01), with histologic improvements in granulation tissue and neovascularization.

Conclusions: Diabetes functionally impairs MSCs and dermal regeneration by inhibiting NRF2 nuclear translocation & ROS scavenging. Topical Keap1 a rapidly-translatable therapy with significant clinical promise to restore redox homeostasis and accelerate diabetic wound closure


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