Pgc-1α controls epidermal stem cell fate and skin repair by sustaining NAD⁺ homeostasis during aging

The epidermal barrier is renewed by the activation, proliferation, and differentiation of keratinocyte stem cells after injury and aging impedes this repair process through undefined mechanisms. We previously identified a gene signature of metabolic dysfunction in aged murine epidermis, but the precise regulators of epidermal repair and age-related growth defects are not well established. Aged mouse models as well as mice with conditional epidermal loss of the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1α) were used to explore the cellular pathways which control skin repair after injury and stress.

Aged mice or those with epidermal Pgc-1α deletion (epiPgc-1α KO) and young or Pgc1a^fl/fl controls were subjected to wound injury, UVB exposure or the inflammatory agent TPA. In vivo and ex vivo analyses of wound closure, skin structure, cell growth and stem cell differentiation were used to understand changes in epidermal re-growth and repair resulting from aging or Pgc-1α loss.

Aging impairs epidermal re-growth during wound healing and results in lower expression of Pgc-1α. Mice with conditional deletion of epidermal Pgc-1α exhibit greater inflammation- and UVB-induced cell differentiation, reduced proliferation, and slower wound healing. epiPgc-1α KO mice also displayed reduced keratinocyte NAD⁺ levels, shorter telomeres, and greater poly ADP-ribosylation, resulting in enhanced stress-stimulated p53 and p21 signaling. When NAD⁺ was reduced by Pgc-1α loss or pharmacologic inhibition of NAD⁺ synthesis, there was reduced stress-induced proliferation, increased differentiation, and protection against DNA damage via enhanced epidermal shedding. Similarly, aged mice exhibit disrupted epidermal NAD⁺ homeostasis and enhanced p53 activation, resulting in p21 growth arrest after wounding. NAD⁺ precursor treatment restores epidermal growth from old skin to that of young.

Our studies identify a novel role for epidermal Pgc-1α in controlling epidermal repair via its regulation of cellular NAD⁺ and downstream effects on p53-driven growth arrest. We also establish that parallel mechanisms are evident in aged epidermis, showing that NAD⁺ signaling is an important controller of physiologic skin repair and that dysfunction of this pathway contributes to age-related wound repair defects.