Skin specializes in a regional-specific manner, including the formation of distinct types of epidermally-derived glands during development, such as sweat glands in palmoplantar skin, sebaceous glands in hair-bearing skin, and meibomian glands in the eyelid. Our goal is to understand this regional specification. Palmoplantar skin is structurally and functionally unique, but 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 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 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 across 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.

In the eyelid, meibomian glands have received interest based on the association of observable gland dysfunction with dry eye disease. In particular, gland atrophy and changes in lipid quality are recognized as causing abnormal tear film break-up, leading to hyperosmolarity of the ocular surface, corneal epithelial damage and ocular surface inflammation. Here, we use single-cell and spatial transcriptomic approaches to characterize and spatially map the murine eyelid, with a particular focus on the meibomian gland. We identify sequential activation of lipid synthesis factors in meibocyte differentiation at the single cell level which we then validate spatially. Next, using an Awat2 KO mouse model, we characterize transcriptomic alterations, including an increase in immune populations and activation of psoriasis-like inflammatory pathways during meibomian gland dysfunction. Within the meibomian gland, we find marked expansion of the ductal epithelia and a shift in the meibocyte differentiation program. Finally, we identify a heightened immune environment in the aging eyelid, which is consistent both in healthy and KO mice.