Regeneration of epithelial appendages in adult organs is very rare and difficult to achieve, and the underlying molecular mechanisms are poorly understood. In skin, it remains a major clinical challenge to generate replacement skin with hair follicles, which would be highly desirable from a functional and cosmetic perspective. We recently uncovered that activation of a single signaling pathway in the dermis was sufficient to reprogram epithelial cells in adult mouse skin so that they re-enter an embryonic hair follicle developmental program. The aim of this research program is to reveal the molecular mechanisms governing this adult-to-embryonic-state reprogramming. We will use a combination of mouse models for cell-specific signal activation and cell-fate mapping, and single-cell transcriptomics of mouse embryonic and adult skin. This project will not only address the importance of the local microenvironment for organ regeneration in an adult setting, but also holds high promise for a leap forward in regenerative medicine by demonstrating how to induce new hair follicles in replacement skin for patients in need.