Single-cell transcriptomics of human skin reveals age-associated specificity of distinct cell populations

Abstract

Background

The skin, as the body’s largest organ, undergoes significant changes with aging, impacting its structural integrity, repair capacity, and immune function. Previous studies have highlighted the heterogeneity of skin cells, particularly fibroblasts, and their role in skin homeostasis. However, the molecular and functional dynamics of these cell populations during aging, especially in sun-protected areas, remain underexplored. This study aims to elucidate the age-related changes in skin cell populations, focusing on dermal fibroblasts, using single-cell RNA sequencing (scRNA-seq) to provide insights into the mechanisms of intrinsic skin aging.

Methods

We utilized single-cell RNA sequencing (scRNA-seq) to analyze skin samples from healthy human donors. A total of over 5,000 cells were included in the study, representing a variety of skin cell types, including fibroblasts, keratinocytes, and immune cells. To further investigate the biological functions and differences between cell types, we performed differential gene expression analysis, Gene Ontology (GO) enrichment, and KEGG pathway analysis. Additionally, pseudotime analysis was conducted to examine cellular differentiation trajectories, while CellChat analysis was used to assess intercellular communication in the skin. These methodologies allowed us to identify key cell populations, their functional properties, and the impact of aging on skin cell interactions.

Results

Study revealed significant diversity and functional specialization among skin cells, defining several major cell subgroups. These subgroups exhibited specific spatial localization in different regions of the skin and demonstrated distinct functional characteristics, such as secretion, mesenchymal activity, and immune regulation. Importantly, we found that with aging, there is a general reduction in the “activation” (i.e., activity and functionality) of skin cells. Aging not only affects individual cell types, such as fibroblasts, but also leads to a marked decrease in interactions between different skin cell types, including cell communication at the dermal-epidermal junction. These findings highlight the complexity of skin aging as a process involving multiple cell types and their interactions.

Conclusion

Our work provides new insights into the functional specialization and aging process of skin cells. We identified a key age-related change in human skin: the partial loss of cell identity and function. These findings contribute to the understanding of skin aging mechanisms and associated phenotypes, offering potential directions for future anti-aging therapeutic strategies.