Fibroblast Lineage Switching as the Developmental Origin of Scarring and Target for Regenerative Healing.

Responses to cutaneous injury differ fundamentally across developmental stages in several mammal species. During early human gestation, when the fetus is less than 24 weeks old, wounds are capable of restoring normal tissue architecture without forming fibrotic scars. In contrast, postnatal and adult injuries typically resolve through the process of fibrosis. This divergence reflects coordinated differences in epidermal and dermal compartments, inflammatory signaling, extracellular matrix (ECM) composition, mechanical cues, and gene regulation. Recent studies have demonstrated that dermal fibroblasts are no longer considered a uniform population but instead arise from distinct developmental lineages with stable functional identities. Engrailed-1-negative fibroblasts (ENFs) predominate in early fetal skin in mice and support regenerative repair, while Engrailed-1-positive fibroblasts (EPFs) emerge later in development and are the principal contributors to fibrotic matrix deposition following injury. The developmental shift between these fibroblast populations coincides with the loss of scar-free healing capacity. This review examines the current understanding of fibroblast lineage specification, with particular emphasis on the roles of mechanotransduction, extracellular matrix cues, and epigenetic regulation. Elucidating how these lineage-encoded programs are established and maintained may enable strategies to reprogram adult fibroblasts toward a fetal-like regenerative state and thereby promote scar-free tissue repair.