Regeneration without scarring
Wounds in adult mammals typically heal by forming fibrotic scars. Mascharak et al. found that a specific population of skin fibroblasts (Engrailed-1 lineage–negative fibroblasts) activate expression of Engrailed-1 and turn on profibrotic cellular programs in response to local tissue mechanics in wounds (see the Perspective by Konieczny and Naik). When mechanical signaling was inhibited in these cells (using either genetic deletion or small-molecule inhibition), skin wounds in mice no longer formed scars but instead healed by regeneration, restoring skin with normal hair follicles and glands, extracellular matrix, and mechanical strength.
INTRODUCTION
Skin wounds generally heal by scarring, a fibrotic process mediated by the Engrailed-1 (En1) fibroblast lineage. Scars differ from normal unwounded skin in three ways: (i) They lack hair follicles, sebaceous glands, and other dermal appendages; (ii) they contain dense, parallel extracellular matrix fibers rather than the “basket-weave” pattern of uninjured skin; and (iii) as a result of this altered matrix structure, they lack skin’s normal flexibility and strength. A successful scar therapy would address these three differences by promoting regrowth of dermal appendages, reestablishment of normal matrix ultrastructure, and restoration of mechanical robustness. However, little is known about the cellular and molecular mechanisms blocking a regenerative healing response in postnatal skin, or whether these mechanisms can be bypassed by modulating specific fibroblast lineages.
