Skin wound repair is a complex process that requires intricate coordination of different cell types to bring about healing. Delayed wound healing or excessive scarring are consequences of an impaired healing process and represent a major health and economic burden worldwide. Circular RNAs (circRNAs) are a family of transcripts with unique structures - the 3’ and 5’ ends are joined together through a process called back-splicing. CircRNAs were shown to be more stable and have tissue specific expression patterns and diverse modes of action. Yet there are hardly any studies that address their functional roles in skin repair. Here we perform expression profiling of circRNAs in skin and wound biopsies as well as in fibroblasts and keratinocytes isolated from skin and acute wounds. We identify the circular RNA circGLIS3 that is upregulated and has a dynamic expression pattern in the dermis of acute wounds compared to intact skin, and its expression is induced by IL-1α in fibroblasts. At a subcellular level, circGLIS3 mainly resides in the cytoplasm of fibroblasts where it interacts with Procollagen C-endopeptidase enhancer 1 (PCPE-1) to boost TGF-β signaling, leading to fibroblast activation and ECM production. Knockdown of circGLIS3 in human ex vivo wounds delays re-epithelialization and reduces contraction, reinforcing the beneficial role of circGLIS3 for skin wound closure. Further investigations on the biological role of circGLIS3 in pathological conditions could enable the development of innovative and more effective therapies for abnormal scarring or nonhealing wounds.

ESDR351 - The circular RNA circGLIS3 activates dermal fibroblasts and increases ECM production to improve wound healing

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING