miR-23a-3p Causes Cellular Senescence by Targeting Hyaluronan Synthase 2: Possible Implication for Skin Aging

Even though aging and cellular senescence appear to be linked, the biological mechanisms interconnecting these two processes remain to be unravelled. Therefore, microRNA (miRNA/miR) profiles were analyzed ex vivo by means of gene array in fibroblasts isolated from young and old human donors. Expression of several miRNAs was positively correlated with donor age. Among them, miR-23a-3p was shown to target hyaluronan synthase 2 (HAS2). HA is a polysaccharide of the extracellular matrix that critically regulates the phenotype of fibroblasts. Indeed, both aged and senescent fibroblasts showed increased miR-23a-3p expression and secreted significantly lower amounts of HA compared with young and non-senescent fibroblasts. Ectopic overexpression of miR-23a-3p in non-senescent fibroblasts led to decreased HAS2-mediated HA synthesis, upregulation of senescence-associated markers, and decreased proliferation. In addition, siRNA-mediated downregulation of HAS2 and pharmacological inhibition of HA synthesis by 4-methylumbelliferone mimicked the effects of miR-23a-3p. In vivo, miR-23a-3p was upregulated and HAS2 was downregulated in the skin of old mice compared with young mice. Inhibition of HA synthesis by 4-methylumbelliferone in mice reduced dermal hydration and viscoelasticity, thereby mimicking an aged skin phenotype. Taken together, these findings appear to link miR-23a-3p and the HA microenvironment as effector mechanisms in both dermal aging and senescence.