Young fibroblast-derived migrasomes alleviate keratinocyte senescence and enhance wound healing in aged skin.

BACKGROUND: Alterations in intercellular communication driven by cellular senescence constitute an important factor in skin aging. Migrasome, a newly discovered vesicular organelle, efficiently participates in intercellular communication; however, the relationship between cellular senescence and migrasomes remains unreported. OBJECTIVE: This study aims to explore the possible relationship between cellular senescence and migrasomes formation, and investigate the effects of young fibroblast-derived migrasomes on senescent keratinocytes and wound healing in aged skin. RESULT: Single-cell RNA sequencing (scRNA-seq) data analysis revealed that fibroblasts exhibited the highest level of transcriptional variability during skin aging, and the degree of fibroblast senescence negatively correlated with the expression level of migrasome-associated markers. Further multiplex Immunohistochemistry (mIHC) results suggested that younger mouse skin contained more migrasomes than older mouse skin. Transmission electron microscopy (TEM) observations demonstrated abundant migrasomes in the skin from young individuals. In vitro experiments indicated that young fibroblasts produced significantly more migrasomes than senescent fibroblasts, as confirmed by wheat germ agglutinin (WGA) staining and scanning electron microscopy (SEM). Importantly, purified migrasomes from young fibroblasts were found to reduce the expression of senescence-associated markers in HaCaT cells. In vivo, using a wound healing model in naturally aged mice, we observed that migrasomes derived from young fibroblasts not only accelerated wound healing but also reduced senescence-associated marker expression in the skin. CONCLUSION: Migrasomes formation ability reduced during skin aging progress, and young fibroblast-derived migrasomes rejuvenated senescent keratinocytes and promoted wound healing in aged skin. These findings offer new ideas for alleviating skin aging and enhancing wound healing in aged skin.