Epigenetic Regulation of Skin Regeneration

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SUMMARY Defective wound healing accounts for enormous morbidity and fiscal burden worldwide. Chronological aging of skin is at the foundation of defective wound healing, although little is known regarding the underlying cause of this association. However compelling data indicates that skin stem cells that become deficient as we age are the basis for defective wound healing. Moreover, reversible epigenetic regulation plays a critical role in stem cell health and maintenance. We therefore posit that the fundamental underpinnings of regenerative healing of skin reside in the epigenetic regulation of skin stem cells. Here, we propose to study epigenetic changes in skin regeneration in wound healing and aging, and test a newly discovered form of in vivo epigenetic reprogramming that we predict will reverse the age and restore function to aging stem cells. Thus, the primary goal of this project is to elucidate epigenetic mechanisms of skin stem cell regulation with focus on DNA methylation/hydroxymethylation and histone modification, and to develop novel and practical translational approaches to reprogramming age-related stem cell epigenetic aberrances. We have assembled a synergistic interdisciplinary team of investigators with a history of pioneering discovery in the areas of aging biology, epigenetics, epigenetic reprogramming, skin stem cell biology, dermatopathology and biomarker application. We also have developed experimental models that encompass biodegradable wound healing scaffold development, human skin xenotransplantation, three-dimensional bioprinting, and a mouse model of epigenetically inducible premature aging. Thus, we will leverage multiple points of synergy, experience, and collaborative interaction to tackle the complex and clinically important questions of age-related wound healing deficiency. Most importantly, we will define and test the therapeutic effects of epigenetic reprogramming in our novel and complementary pre-clinical model systems. This proposal presents a new approach of epigenetic reprogramming of functionally deficient aging stem cells to enhance skin regeneration in order to heal chronic wounds in the aging populace. If successful, such an approach could transform the way we think about the aging process and treating age-related skin disorders.