Differential cell composition and split epidermal differentiation in human palm, sole, and hip skin

Palmoplantar skin is structurally and functionally unique, but the transcriptional programs driving this specialization are unclear. Here, we use bulk and single-cell RNA sequencing of human palm, sole, and hip skin to describe the distinguishing characteristics of palmoplantar and non-palmoplantar skin while also uncovering differences between palmar and plantar sites. Our approach reveals an altered immune environment in palmoplantar skin, with downregulation of diverse immunological processes and decreased immune cell populations. Further, we identify specific fibroblast populations that appear to orchestrate key differences in cell-cell communication in palm, sole, and hip. Dedicated keratinocyte analysis highlights major differences in basal cell fraction among the three sites and demonstrates the existence of two spinous keratinocyte populations constituting parallel, site-selective epidermal differentiation trajectories. In summary, this deep characterization of highly adapted palmoplantar skin contributes key insights into the fundamental biology of human skin and provides a valuable data resource for further investigation. [Display omitted] •Find differences between palmoplantar and non-palmoplantar skin and palm and sole skin•Report an altered immune environment in the palmoplantar skin•Characterize a palmoplantar-specific fibroblast population•Identify two parallel site-selective epidermal differentiation trajectories Wiedemann et al. present a comprehensive characterization of human palmoplantar skin. They find a dampened palmoplantar immune environment, describe differences between palmar and plantar skin, characterize a distinct palmoplantar fibroblast population marked by differential cell-cell signaling, and identify a site-selective dual epidermal differentiation trajectory.