Single cell deciphering of pruritic keloids: the interaction between fibroblasts and Schwann cells through the Midkine signaling

Background: Keloids are a common skin fibroproliferative disease that can result in severe aesthetic and functional concerns. Pruritus and pain are the most prevalent clinical manifestations of keloids. Schwann cells (SCs) variation and neuropathy within keloids contribute to these uncomfortable sensations; however the underlying mechanisms remain unclear. This study aims to explore the potential role of fibroblasts (FBs) and SCs in pruritic and pain keloids. Methods: The activity of FBs and SCs was investigated using single-cell RNA sequencing (scRNA-seq) data of keloids. These bioinformatics analysis results were validated through in vitro cell culture, clinical samples, and in vivo experiments. The selected molecule was confirmed to be correlated with pain and itch and was subsequently used to treat cells in order to investigate its role in keloids. The in vivo inhibition assay was performed to evaluate its therapeutic potential. Results: Our scRNA-seq analysis identified specific types of FBs and SCs were present in higher proportions in keloids and exhibited neurogenesis-related functions. Upon conducting an interaction analysis of these two cell types, we identified a critical molecule, Midkine (MDK), which is positively correlated with the patients' pain and itching levels. Besides, MDK treatment facilitated the proliferation of SCs and their transition to a repairing phenotype, resulting in neuronal axonogenesis. This activation of repairing SCs promoted the release of substance P from nerve fibers, leading to clinical symptoms of pain and pruritus in keloid patients. Targeting MDK effectively reduces abnormal Schwann cell proliferation and subsequently inhibits the secretion of neuropeptides that trigger pain and pruritus. Conclusions: Our study uncovered the interaction between FBs and SCs in the development of keloidal pain and pruritus, offering a novel therapeutic strategy to alleviate the distressing symptoms of keloids.