Dermal fibroblasts retain site-specific transcriptomic identity in keloids

Abstract

BackgroundHuman skin displays extensive spatial heterogeneity and maintains distinct positional identity. However, the impact of disease processes on these site-specific differences remains poorly understood, especially in keloid, a skin disorder characterized by pronounced spatial heterogeneity. ObjectiveThis study aimed to assess whether the spatial heterogeneity and positional identity observed in different anatomic sites persist in keloids. MethodsTranscriptome sequencing was conducted on 139 keloid dermal tissues and 19 keloid fibroblast samples spanning seven distinct anatomic sites to identify the spatial transcriptomic heterogeneity. In addition, single-cell RNA sequencing data were utilized to elucidate the contributions of various cell types to the maintenance of positional identity. ResultsKeloid dermal tissues from diverse sites were categorized into three anatomic groupings: trunk and extremity, ear, and mandible regions. Enrichment analysis of differentially expressed genes unveiled that keloids across distinct regions retained unique anatomically-related gene expression profiles, reminiscent of those observed in normal skin. Notably, regional disparities consistently prevailed and surpassed inter-donor variations. Single-cell RNA sequencing further revealed that mesenchymal cells, particularly fibroblasts, made major contributions to positional identity in keloids. Moreover, gene expression profiles in primary keloid fibroblasts demonstrated a remarkable persistence of positional identity, enduring even after prolonged in vitro propagation. ConclusionTaken together, these findings imply that keloids remain positional identity and developmental imprinting characteristic of normal skin. Fibroblasts predominantly contribute to the spatial heterogeneity observed in keloids.