Research Article: MicroRNA-152 and -181a participate in human dermal fibroblasts senescence acting on cell adhesion and remodeling of the extra-cellular matrix

Date Published: November 9, 2012

Publisher: Impact Journals LLC

Author(s): Mara Mancini, Gaelle Saintigny, Christian Mahé, Margherita Annicchiarico-Petruzzelli, Gerry Melino, Eleonora Candi.

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Abstract

Ageing of human skin is associated with phenotypic changes in the cutaneous cells; the major functional markers of ageing occur as consequences of dermal and epidermal cell senescence and of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. Understanding the contribution of the dermal cells in skin ageing is a key question, since this tissue is particularly important for skin integrity and its properties can affect the epidermis. Several microRNAs have been shown to be involved in the regulation of pathways involved in cellular senescence and exerted important effects on tissues ageing. In this study, we demonstrate that the expression of miR-152 and miR-181a increased during the human dermal fibroblasts senescence and that their overexpression, is sufficient to induce cellular senescence in early-passage cells. The increase of these miRNAs during cells senescence was accompanied by a decrease in integrin α and collagen XVI expression at mRNA and/or protein levels resulting in reduced cellular adhesion and suggesting extracellular matrix remodeling. These findings indicate that changes in miRNAs expression, by modulating the levels of adhesion proteins and extra-cellular matrix components, such as integrin α and collagen XVI, could contribute to the compositional remodelling of the dermis and epidermis occurring during skin aging.

Partial Text

Senescence is a biological state in which the cells have an irreversible proliferative arrest while they continue to be metabolic active. The senescent phenotype is acquired in vitro after multiple rounds of cell division (replicative senescence) or upon oncogenes activation or oxidative stress (stress-induced premature senescence) [1-8]. The mechanisms underlying replicative senescence include telomere shortening, permanent growth arrest from G1 to S phase of the cell cycle, enhanced beta-galactosidase activity and increased expression of key mediators including p53, promyelocitic leukemia protein (PML), p16INK4a and p19Arf [1,9-12]. While cellular senescence is considered a protective mechanism against cancer, it has also been hypothesized that the progressive accumulation of senescent cells in some tissues may contribute to several age-related diseases and organismal aging [13-15]. Progressive DNA damage and mitochondrial decline are both considered to be prime instigators of natural ageing. These two pathways have been viewed largely in isolation. However, recent studies have revealed a molecular circuit that directly links DNA damage to compromised mitochondrial biogenesis and function via p53 [16-22]. Furthermore, the mitochondrial function decline is considered a major mechanism underlying senescence. Damaged mitochondria not only produce less ATP but also generate increased amounts of reactive oxygen species and display a greater propensity to trigger apoptosis [23-29].

Here, we have identified two miRNAs, miR-152 and miR-181a, upregulated in senescent human diploid fibroblasts. We have also shown that 3-5 fold expression of the two miRNAs is sufficient per se to induce senescence markers (SA-β-gal staining, reduced cell proliferation and expression of p16INK4a) in proliferating, young fibroblasts. We have identified ITGA5 as direct targets of miR-152. Integrins, beside transducing signals from the matrix to cells, bind to ECM to allow the fibroblasts to organize and remodel the matrix [81], this features is very limited in aged tissues and in particular in aged skin and this could be due in part to ITGA5 downregulation mediated by miR-152. In addition, we have shown that overexpression of miR-152 in fibroblasts significantly reduced cell adhesion, this finding indicate that ITGA5 might have a role in aged skin tissue. On the other hand, miR-181a target is COL16A1 mRNA, collagen XVI is a minor component of the skin ECM, nevertheless it is expressed in the DEJ zone of the papillary dermis and it connects ECM proteins to cells, ensuring mechanical anchorage of the cell and outside-inside signal transduction [85, 86]. Overall, these findings suggest a model whereby during replicative senescence, a set of miRNAs, among them miR-152 and miR-181a, are upregulated, this sustain the senescent phenotype. The mechanisms through which the miRNAs are upregulated will deserve further investigation. Although we do not exclude the possibility that other important senescence-associated miRNA-152 and miR-181a targets play a role in the senescent phenotype observed, we believe that the reduction in expression of ITGA5 and COL16A1 by miR-152 and miR-181a, strongly suggests that miRNAs have a complex role also in ECM remodeling typical of aged skin that deserve to be further investigated.

 

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