A multi-omic single-cell landscape of perinatal mouse skin maps lineage specification and reveals shared dynamics in human fetal skin.

During the hair cycle and wound regeneration, various developmental transcriptomic features are reactivated. Consequently, studying skin development provides critical insights into both fundamental biology and skin regeneration. However, chromatin accessibility during skin development remains underexplored. To address this gap, we conducted integrated single-cell chromatin and transcriptomic analyses of developing mouse skin. Our investigation revealed key gene network axes underlying skin lineage specification. In particular, our multi-omics approach identified Mef2c+ upper fibroblasts as putative precursor cells for smooth muscle-like appendages, such as the arrector pili muscle. Furthermore, leveraging the fetal human skin atlas, we uncovered strong cross-species correlations between mouse and human skin during development. We identified an MEF2C+ fibroblast counterpart in human fetal skin and further delineated fibroblast lineages, including dermal sheath and arrector pili muscle, demonstrating that fibroblast developmental timelines are conserved between mouse and human. Together, this study establishes a robust, human-translatable foundation for future investigations into skin development and regeneration.