Single-cell RNA sequencing reveals the heterogeneity and intercellular communication of endothelial cells and Schwann cells during keloid formation.

Abstract

Keloids are benign fibrous lesions characterized by tumor-like behavior, including continuous expansion beyond the original wound boundaries, absence of natural regression, and a strong tendency to recur after treatment. While cellular heterogeneity and intercellular signaling are recognized contributors to keloid progression, the specific phenotypic transitions and regulatory interactions among involved cell types remain poorly defined. We analyzed transcriptomic profiles from six samples in the GSE163973 dataset, including three keloid and three normal scar tissues. Single-cell RNA sequencing datasets were analyzed to classify cellular populations and to investigate gene expression patterns and ligand-receptor interactions within distinct subgroups. Nine primary cell types were identified: endothelial cells, fibroblasts, smooth muscle cells/pericytes, keratinocytes, macrophage/dendritic cells, lymphatic endothelial cells, T cells, Schwann cells, and melanocytes. Among these, endothelial cells and Schwann cells showed the greatest transcriptional variability. Subcluster analysis and ligand-receptor mapping revealed pronounced heterogeneity and complex intercellular communication within keloid tissues. Notably, one subcluster of keloid endothelial cells shared transcriptional features with endothelial cells in cutaneous malignant tumors and demonstrated strong migratory potential. PLPP3 was identified as a key regulator of endothelial tubulogenesis within this subpopulation. This study highlights the distinct heterogeneity and dynamic intercellular interaction between endothelial cells (ECs) and Schwann cells (SCs) in the pathogenesis of keloids. The identification of tumor-like endothelial subclusters and their regulatory networks provides novel insights into keloid biology and suggests PLPP3 as a potential target for therapeutic intervention.