Controlling the epigenetic switch of skin fibroblast aging

The aging-related decline in the skins function is a major cause of morbidity and risk factor for skin fragility, infections, impaired wound healing, and skin cancer. Aging -dependent skin alterations are associated with significant changes of the connective tissue and dermal fibroblasts, an important cell type that keeps our skin smooth and elastic. Fibroblasts display an unprecedented heterogeneity and plasticity, but how fibroblast fate decisions are controlled is unknown. We aim at investigating if their differentiation programs in skin homeostasis and aging are controlled epigenetically. Identification of the epigenetic switches regulating the balance between fibroblast proliferation, differentiation and senescence could help to counteract skin aging and associated defects in wound healing. We will perform Single-cell-Assay-for-Transposase-Accessible-Chromatin (scATAC) and single-cell-RNA sequencing (scRNA-Seq) of fibroblasts isolated from human skin of young and old donors followed by a range of in-vitro and in-vivo assays to determine the epigenome and transcriptome of young and aged, pathogenic fibroblasts. Our studies will unravel if fibroblast differentiation programs are controlled by reversible epigenetic marks, and reveal if targeting these epigenetic switches by pharmacological drugs could be used to resolve aging-mediated defects of skin function, for example by reprogramming senescent or fibrotic fibroblasts, thereby rejuvenating the skin dermis and improving wound repair, especially in the elde rly.