Aging epidermis in the epidermis is marked by decreases in both cell replication and production of proteins necessary for epidermal integrity. The epidermis thins, cracks and has a significantly reduced barrier function. Intrusion of chemicals and microbes increases; underlying connective tissue becomes more easily desiccated. There is poor resistance to physical trauma and inefficient wound repair. It is of little surprise that three-quarters of patients with decubitus ulcers (pressure sores) are over the age of seventy. Our long-term goal is to improve day- to-day cutaneous health and geriatric wound healing by identifying mechanisms of pharmacological or dietary compounds that enhance keratinocyte replacement or epidermal repair. We have recently demonstrated that a group of synthetic and natural compounds known as peroxisome proliferators (PPs) can increase epidermal keratinocyte growth. We hypothesize that PPs may unequally afect the different sub populations of replication competent keratinocytes. Epidermal replacement is dependent on replication of rare keratinocyte stem cells and more abundant transient amplifying cells.
The Specific Aim for this pilot study will focus on detecting possible shifts in these populations. Keratinocytes will be treated with PPs and examined for changes in i)serial growth capacity in clonogenic assays and ii)expression of differentiation-dependent biochemical markers. Results within each assay can distinguish keratinocyte subpopulations of transient amplifying cells versus putative keratinocyte stem cells. PP exposure may increase the transient amplifying compartment by increasing the number of rounds of replication usually limited to 2-3 before withdrawal from the cell cycle and/or induce qualitative and/or quantitative changes in a6 and (31 integrins, proteins known to be essential for maintaining stem cell potential. Future work could address other cell cycle parameters and cellular responses to decipher the PP-induced growth enhancement. A better understanding of PP effect on keratinocyte replication may provide improved clinical interventions aimed at maintenance of geriatric cutaneous health and/or decreased time for skin wound-healing.
