Genome-wide profiling of adult human papillary and reticular fibroblasts identifies ACAN, Col XI α1, and PSG1 as general biomarkers of dermis ageing, and KANK4 as an exemplary effector of papillary fibroblast ageing, related to contractility

Abstract

Deciphering the characteristics of dermal fibroblasts is critical to further understand skin ageing. We have conducted a genome-wide transcriptomic characterization of papillary (Fp) and reticular (Fr) fibroblasts extracted from human skin samples corresponding to younger and older adult ages. From this screen, biomarkers suitable for the assessment of chronological ageing were identified, and extrapolated to the context of photo-damaged skin. In particular, KANK4, ACAN, Col XI α1, and PSG1, were expressed at an increased level in both chronologically-aged and photo-damaged skin. Notably, analysis focused on Fp identified significant transcriptional signatures associated with ageing, which included transcripts related to extracellular matrix, focal adhesion points, and cytoskeleton, thus suggesting functional consequences on tissue structure. At a cellular level, an increased contractility was identified as a property of aged Fp. Accordingly, further investigations were conducted on the KN motif and ankyrin repeat-containing protein 4 (KANK4) to explore its possible function as an original effector involved in the acquisition of aged properties in Fp, notably their increased contractility. We show that KANK4 down-modulation using siRNA led to increased Rho pathway activity, thereby reducing their contractility. As a proof-of-principle, the present study shows that targeting KANK4 was efficient to attenuate aged Fp characteristics.