Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing

Abstract

Abstract Aged skin wounds heal poorly, resulting in medical, economic, and social burdens posed by nonhealing wounds. Age-related defects in repair are associated with reduced myofibroblasts and dysfunctional extracellular matrix (ECM) deposition. Bidirectional cell-cell communication involving exosome-borne cargo such as micro RNAs (miRs) has emerged as a critical mechanism for wound healing and aged tissue regeneration. Here we report that at the wound edge, aged fibroblasts display reduced migration and differentiation into myofibroblasts, with impaired ECM deposition, when compared with young tissue. Proper activation of fibroblasts to myofibroblasts may alleviate age-related defects in wound healing. Herein, an exosome-guided cell technique was performed to induce effective wound healing. Supplementing wounds with exosomes isolated from young mouse wound-edge fibroblasts (exosomesYoung) significantly improved the abundance of myofibroblasts and wound healing in aged mice and caused fibroblasts to migrate and transition to myofibroblasts in vitro. To determine the underlying mechanism, we found that exosomal transfer of miR-125b to fibroblasts inhibited sirtuin 7 (Sirt7), thus accelerating myofibroblast differentiation and wound healing in aged mice. Notably, after epidermal inhibition of miR-125b or overexpression of Sirt7 in fibroblasts, migration and myofibroblast transition were perturbed. Our findings thus reveal that miR-125b is transferred through exosomes from young fibroblasts to old fibroblasts contributes to promoting fibroblast migration and transition to counteract aging, suggesting a potential avenue for anti-aging interventions in wound healing. Graphical Abstract

Keywords

• Wound healing
• Exosome induced microRNA delivery
• Senescence
• Fibroblast to myofibroblast transition
• ECM deposition