A single-cell transcriptome atlas of pig skin reveals cellular heterogeneity from embryonic development to postnatal aging.

Background: Mammalian skin exhibits profound cellular and molecular restructuring across lifespan, yet an integrated single-cell mapping from embryogenesis to senescence remains limited. The Chenghua (CH) pig, with exceptional skin thickness characteristics, provides a promising model for investigating human skin development and physiology.

Results: We constructed a comprehensive single-cell RNA atlas of 443,529 cells from CH pig skin spanning 10 developmental stages (embryonic day 56 to postnatally year 7). Our analysis identified eight major skin cell types and revealed stage-specific shifts in cellular composition. Fibroblasts (FBs) and mesenchymal stem cells (MSCs) dominated embryonic development while smooth muscle cells and endothelial cells increased postnatally, with aging marked by FB dysfunction and significant dermal thinning. Pseudotime trajectory analysis identified that FBs differentiated from a common progenitor with MSCs, diverging into five functionally distinct subpopulations including papillary, reticular, mesenchymal, pro-inflammatory, and a novel AUTS2⁺ subtype with neuromodulatory roles. Critically, FBs regulated postnatal skin aging via COL1A1-(ITGA1 + ITGB1) and MDK-SDC1 interaction signaling pathways, with the transcription factor EGR1 regulating collagen-related genes (DPT, COL12A1, COL5A2) during development; the age-dependent suppression of FBs coincided with collagen downregulation, reduced intercellular communication, and elevated transcriptional noise. Concurrently, immune cells including dendritic cells (DCs) and T cells (TCs) exhibited a marked decrease of cell numbers perinatally, with cytotoxic NKT cells reaching peak abundance at rapid growth stage; DCs and TCs primarily utilized SPP1 and TGF-β signaling pathways to regulate skin immunity during development and aging. Cross-species analysis confirmed the evolutionary conservation of skin cell types and FB functional gene profiles related to ECM deposition and inflammatory responses across pigs, humans, and mice during development and aging.

Conclusions: This work delineates cellular dynamics underpinning skin homeostasis, uncovers the vital physiological functions of FBs and immune cells during skin development and aging, and validates the pig model for human cutaneous physiology research. The atlas serves as a pivotal resource for skin mechanistic and translational studies.