Abstract
Multiple factors and conditions can lead to impaired wound healing. Chronic non-healing wounds are a common problem among the elderly. To identify microRNAs negatively impacting the wound repair, global miRNA profiling of wounds collected from young and old mice was performed. A subset of miRNAs that exhibited an age-dependent expression pattern during wound closure was identified, including miR-31 and miR-200c. The expression of miR-200 family members was markedly downregulated upon wounding in both young and aged mice, with an exception of acute upregulation of miR-200c at the early phase of wound healing in aged skin. In unwounded aged skin (versus unwounded younger skin), the level of miR-200c was also found elevated in both human and mice. Overexpression of miR-200c in human ex vivo wounds delayed re-epithelialisation and inhibited cell proliferation in the wound epithelium. Modulation of miR-200c expression in both human and mouse keratinocytes in vitro revealed inhibitory effects of miR-200c on migration, but not proliferation. Accelerated wound closure in vitro induced by anti-miR-200c was associated with upregulation of genes controlling cell migration. Thus, our study identified miR-200c as a critical determinant that inhibits cell migration during skin repair after injury and may contribute to age-associated alterations in wound repair.
Highlights
A class of non-coding RNA molecules that have recently emerged as critical factors in wound healing are the microRNAs11–13. miRNAs are about 22-25 nucleotides in length and affect a wide range of cellular processes. miRNAs function by inhibiting mRNA translation or by targeting mRNA for degradation[14,15,16,17]
The objective of the current study was to identify expressional changes of miRNAs during wound healing in aged versus young skin using mouse model, and to define the role for distinct miRNAs in the control of keratinocyte proliferation, migration and differentiation that might contribute to the age-associated alterations in cutaneous wound healing
In order to identify the candidate miRNAs that might compromise wound healing and contribute to the age-associated delay in wound repair, global miRNA profiling was performed in mouse back telogen skin of young (8-week-old) and aged (2-year-old) animals at distinct time points after wounding (Supplementary Table 1a,b)
Summary
A class of non-coding RNA molecules that have recently emerged as critical factors in wound healing are the microRNAs (miRNAs)11–13. miRNAs are about 22-25 nucleotides in length and affect a wide range of cellular processes. miRNAs function by inhibiting mRNA translation or by targeting mRNA for degradation[14,15,16,17]. The Tomic-Canic lab identified a candidate set of microRNAs that contributes to the chronic non-healing wounds[13]. They observed enhanced levels of miR-21 and miR-130 in venous ulcers patients, which delay healing of human wounds by targeting leptin receptor (LepR)[13]. MiRNAs have emerged as key players in skin repair, their contribution to the aged-associated changes in the skin and impairment in wound healing remains unknown. The objective of the current study was to identify expressional changes of miRNAs during wound healing in aged versus young skin using mouse model, and to define the role for distinct miRNAs in the control of keratinocyte proliferation, migration and differentiation that might contribute to the age-associated alterations in cutaneous wound healing
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