Cyclin-dependent kinase 1 (CDK1)-loaded extracellular vesicles promote wound healing in diabetic obese mice

Summary: Abstract Body: Small extracellular vesicles (sEVs) mediate intercellular signaling to coordinate proliferation of cell types that promote re-epithelialization of skin following injury. Cyclin-dependent kinase 1 (CDK1) drives cell division and is a key regulator of cell cycle. To understand the potential of sEV-mediated delivery of CDK1 to reverse impaired wound healing, we generated CDK1-loaded sEVs (CDK1-sEVs) and evaluated their ability to mediate cell proliferation, re-epithelialization and downstream signaling responses in the wound bed. We found that treatment of human keratinocytes with CDK1-sEVs increased phosphorylation of the CDK1 target, eukaryotic translation inhibition factor 4E-binding protein 1 (4E-BP1), and histone H3 within 24 hours via AKT and ERK phosphorylation, driving increased proliferation and cell migration. Treatment of the wound bed of diabetic obese mice, a model of delayed wound healing, with a single (or repeated) dose of CDK1-sEVs accelerated wound closure, increased re-epithelialization, and promoted keratinocytes proliferation. These studies show that delivery of CDK1 by sEVs can stimulate selective and transient proliferation of keratinocytes to increase re-epithelialization and accelerate wound healing. Wooil Choi¹, Dong Jun Park¹, Keita Nakatsutsumi¹, Robert A. Dorschner², Michelle Yi¹, Brian P. Eliceiri^{2, 1} 1. Surgery, University of California San Diego, La Jolla, CA, United States. 2. Dermatology, University of California San Diego, La Jolla, CA, United States. Translational Studies: Cell and Molecular Biology