Profiling microRNAs in skin wound healing: A new insight into the inflammation-proliferation transition mechanism

Background Wound healing is a highly dynamic and complex biological process that involves tightly regulated phases of inflammation, proliferation, and remodeling. There remains an unmet need to elucidate mechanisms underlying scar formation and to achieve regeneration. MicroRNAs (miRNAs) have emerged as critical regulators of these processes. This study examines the roles of miRNAs during the critical phase of the inflammation-to-proliferation shift in wound healing. Methods We performed miRNA sequencing on wounded skin samples from adult mice, followed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to identify the cellular sources of the most significantly altered miRNAs. Computational analysis was conducted to determine signaling pathways regulated by these miRNAs. Our data were then integrated with other datasets from non-healing (tumor) and regenerative healing (oral mucosal injury) models for comparative analysis. Results Our profiling data identified 532 miRNAs with significant expression changes. FISH and IHC colocalization analyses of the two most differentially expressed miRNAs, miR-654 and miR-147, suggest immune-stromal interactions. Pathway analysis offers further mechanistic insights, emphasizing cellular crosstalk through upregulation of membrane-bound organelles, metabolic status, and TGF-β signaling. KEGG pathway analysis identified endocytosis and lysosomal pathways as the main signaling regulating cellular interactions. Database comparisons across different wound time points and healing models revealed dynamic changes in the top differentially expressed miRNAs, suggesting their context-dependent roles during the inflammation-proliferation transition. To elucidate injury-induced proliferation, we correlated our data with cancer, a condition characterized as a non-healing wound with uncontrolled cell growth. Cross-referencing cancer datasets revealed conserved regulatory mechanisms in which miRNAs transiently co-opted for repair are dysregulated in tumors. Further, database comparisons with oral wound models, which represent scarless regenerative healing, identified specific miRNAs involved in scar formation in skin versus oral mucosal wounds. Conclusion These findings provided mechanistic insights into how the transition from inflammation to proliferation is orchestrated during wound healing, and also identified potential therapeutic targets to enhance healing and achieve scarless regeneration in skin and related tissues.