RNA Coding and Transcriptional Regulation in Skin Repair: Insights from Single-Cell Profiling and Implications for Organoid-Based Regenerative Strategies

Severe skin injury in humans typically heals through fibrotic remodelling rather than true regeneration, resulting in permanent loss of appendages, sensory function, and tissue architecture. Over the past decades, advances in bulk, single-cell, and spatial transcriptomic profiling have revealed that cutaneous wound repair is governed by dynamic, context-dependent gene-regulatory programmes across epidermal, dermal, vascular, and immune compartments. These studies highlight substantial heterogeneity in keratinocyte, fibroblast, and immune cell states, and identify RNA-mediated regulatory networks that bias healing toward either regenerative or fibrotic outcomes. In parallel, stem cell-derived skin organoids and advanced engineered skin equivalents have emerged as experimental platforms capable of reproducing key aspects of human skin organisation, offering new opportunities to move beyond purely reparative grafting strategies. This review integrates evidence from human or murine skin and wound transcriptomics, RNA-based regulatory mechanisms, and organoid-based skin engineering relevant to trauma and burn reconstruction. We summarise how protein-coding and non-coding RNAs (including miRNAs and lncRNAs) coordinate epithelial migration, inflammation resolution, angiogenesis, and ECM remodelling, and how the dysregulation of these networks contributes to pathological scarring. This article synthesises transcriptomic, RNA regulatory, and skin organoid research to propose a conceptual, hypothesis-generating framework for regenerative skin repair, without claiming clinical readiness or validated therapeutic translation.