The age-related alterations of epidermis are essentially characterized by a defect in the tissue renewal caused by a reduced keratinocytes proliferation and by a disturbance of their differentiation. However, the mechanisms disturbing epidermal homeostasis during aging remain poorly understood. To go further into this question, we focused on microRNAs (miRNAs), a class of non-coding RNAs known to play a key role in the regulation of epidermal homeostasis

To identify age-related microRNAs, we performed an exhaustive miRNAs microarray expression screen in human primary keratinocytes from young or elderly peoples. This screening revealed many microRNAs modulated by aging including miR-30a, exhibiting both strands overexpressed in aged cells and tissue. We also observed that miR-30a-3p and -5p were significantly induced in a reconstructed skin model mimicking chronological aging. 

We then constructed a lentiviral vector allowing its inducible and stable overexpression in primary keratinocytes. MiR-30a overexpression lead to a strong impairment of the epidermal differentiation with severe defects of the barrier function in an organotypic culture model. We also observed a significant raise of apoptotic cells in the miR-30a overexpressing epidermis. We then identified several gene targets of miR-30a in keratinocytes, including LOX encoding lysyl oxidase, which plays a role in proliferation/differentiation balance of keratinocytes, IDH1 encoding isocitrate deshydrogenase, a key enzyme of cellular metabolism and AVEN encoding a caspase inhibitor. We confirmed LOX, IDH1 and AVEN direct regulation by miR-30a in human keratinocytes and observed their repression in aged skin, allowing a possible link between miR-30a induction and the skin-aging phenotype. 

Our work revealed a new miRNA actor and deciphered new molecular mechanisms to explain some alterations observed in epidermis during aging, especially those concerning keratinocytes differentiation and apoptotic death.

MiR-30a is an aged-related microRNA that impairs differentiation and induces apoptosis in human epidermis