Ectomesenchyme contributes to epidermal stem cell formation through mesenchymal-to-epithelial transition

Cutaneous development is initiated by crosstalk between non-neural ectodermal epithelium and underlying mesenchymal cells. Recent studies have shown that some mesenchymal cells contribute to keratinocyte regeneration in injured skin. However, whether mesenchymal cells contribute to keratinocyte formation in physiologically normal skin remains unclear. Here we show, using lineage tracing, single-cell transcriptome and epigenome analyses of mouse skin, that the interfollicular epidermis consists largely of mesenchymal-lineage cells. Further lineage-tracing and live-imaging analysis of mouse embryos indicate that these mesenchymal-lineage epidermal progenitor cells arise from ectomesenchyme and contribute to the surface ectoderm through a mesenchymal-to-epithelial transition-like process between embryonic days 8.5 and 9.5. We also establish human induced pluripotent stem cell-derived ectomesenchyme and demonstrate that it generates p63-expressing keratinocytes. These data reveal a previously unappreciated contribution of ectomesenchyme to cutaneous development and provide insight into skin diseases involving epidermal mosaicism.