Therapeutic strategies for scarless skin regeneration after injury

Over 100 million people develop scars each year, and more than 6 million in the United States suffer from chronic, non-healing wounds. Skin is a complex, multi-lineage organ that enables protection, sensation, and thermoregulation, yet after injury, healing is limited to epidermal closure while other cell types are replaced by fibrotic scar. As a result, healed skin remains structurally and functionally impaired. Current therapies focus on infection control and wound closure but do not prevent scarring or restore the cellular diversity required for fully functional skin. A therapy that converts fibrotic repair into true organ-level regeneration represents a major unmet clinical need.

Embryonic skin, however, can fully regenerate after full-thickness injury. By comparing embryonic and postnatal wound healing, we identified CXCL12, produced by postnatal wound fibroblasts, as a key inhibitor of regeneration. Fibroblast-specific deletion of Cxcl12 restores multi-lineage regeneration, establishing CXCL12 as a promising therapeutic target. Unlike other scar-reducing strategies that primarily limit fibrosis, targeting this pathway has the potential to both reduce fibrosis and restore multi-lineage regeneration.

The objective of this proposal is to develop a clinically actionable strategy that leverages CXCL12 biology to enable regenerative wound healing. We will systematically evaluate complementary therapeutic approaches and compare their efficacy, safety, and translational feasibility in preclinical models. These studies will identify the approach with the greatest translational potential and establish key parameters for dosing, delivery, and biological response.