Fibroblasts fluctuating between mesenchyme and epithelium are involved in hair follicle mesenchyme development

The transition between the mesenchyme and epithelium contributes to the development of various tissues. During skin development, epithelial-mesenchymal transition in the ectodermal epithelia is involved in the development of the dermal mesenchyme in early embryos. However, the precise roles and functions of epithelial-mesenchymal/mesenchymal-epithelial transition in cutaneous development have not been fully elucidated. In this study, we aimed to elucidate these roles and functions in the neonatal mouse skin. We conducted single-cell RNA sequencing and immunohistochemical analyses to search for <i>Pdgfra</i>-expressing (<i>Pα</i> ⁺) fibroblasts with transition activities to/from <i>Krt5</i>-expressing keratinocytes. We determined that the <i>Pα</i> ⁺/<i>Krt5</i>-lineage (<i>K5</i> ^lin+) fibroblasts significantly contributed to developing hair follicle dermal stem cells to generate lower dermal papilla cells and lower dermal sheath cells. In the developing mouse skin, <i>K5</i> ^lin ⁺ fibroblasts appeared concurrently with hair follicle development and formed outer edge cells in the early dermal papilla on embryonic day 16.5. <i>K5</i> ^lin ⁺ hair follicle mesenchymal cells were also maintained in aged mouse skin. These results provide insights into the role and function of the transition between the mesenchyme and epithelium in hair follicle development and maintenance.