The consequences of stress on the human organism are well established. Daily life stress mainly impacts the hypothalamic-pituitary-adrenal (HPA) axis, which regulates glucocorticoid (GC) secretion by way of the adrenal gland cortex through adrenocorticotropic hormone (ACTH) released by the hypophysis, under the control of hypothalamic corticotrophinreleasing hormone (CRH) and arginine vasopressin (AVP). Cortisol (the hormone of stress) and dehydroepiandrosterone (DHEA) represent the main GCs in humans and act on specific receptors present in most peripheral tissues, including the skin. Chronic exposure to stressful events leads to excessive stimulation of the HPA axis and hypercortisolemia, which plays a pathophysiological role in the development of a variety of stress-related disorders. In the skin, elevated cortisol induces changes that are similar to those involved in the natural aging process. Locally, 11b-hydroxysteroid dehydrogenases (11b-HSD1 and 2) play a major role in regulating the impact of cortisol in the skin tissue. With the goal to study the impact of elevated cortisol in skin tissue, and more particularly on cellular senescence and repair capacity, 3D bioengineered skin models were developed. The consequences of the exposure of these models to external stresses (UV, pollution.) were also investigated. The innovative skin bioengineered models obtained in this study represent a promising tool for monitoring the impact of elevated concentrations of cortisol on the skin and to identify biofunctional ingredients or chemical substances with modulatory potential in vitro.
305Study of the silencing of a combination of genes involved in cellular senescence in 3D skin bioengineered models C Capallere, C Plaza, C Serre, C Meyrignac and J Botto Ashland, Global Skin Research Center, Sophia Antipolis, France Cellular senescence is an irreversible state of cell cycle arrest that is induced during cellular aging. In the skin, senescence is associated with phenotypic changes in cutaneous structure and cells, lowered resistance to oxidative stress and DNA damage, decreased epidermal cell renewal, decreased synthesis of extracellular matrix protein and the appearance of markers of aging (senescence-associated beta-galactosidase, etc.). Many genes have been reported to be involved in the regulation of senescence: senescence genes, senescence suppressors, oncogenes, tumor suppressors, stemness genes, inflammation-related genes, genes involved in DNA damage repair and cytoskeletal remodeling as well as various transcription factors, ncRNAs and other genes related to epigenetic regulation. In previous studies, we knockeddown various senescence-related genes to induce a senescent phenotype in cultured cells (fibroblasts and keratinocytes) or bioengineered skin models. In this study we performed the combined knock-down of FOXO3A and other genes and we characterized the cellular and tissular consequences by microscopic observation, measurements of the expression level of various proteins and genes, and also the impact on c...
