Mechanical Stretch‐Induced Interlayer Coordination between MMP2 and COL17A1 Exacerbates Regenerative Exhaustion in Skin

Abstract The layered structure of skin necessitates highly sophisticated tissue coordination during regeneration. The unmet clinical need of long‐term skin expansion therapy stems from limited regenerative capacity, yet the underlying mechanism remains enigmatic due to the lack of appropriate animal model. A mouse scalp‐based mechanical stretch model is established that mimics clinical long‐term skin expansion. Prolonged skin expansion progressively drives interfollicular epidermal stem cells towards a state of irreversible regenerative exhaustion, marked by impaired proliferation, differentiation, adhesion, and activity. Mechanistically, mechano‐stress‐induced accumulation of MMP2 in the dermis mediates a shift in extracellular matrix turnover from deposition to degradation, impairing stem cell activity, disrupting niche integrity, and simultaneously triggering proteolysis of COL17A1 at the interlayer. Restoring COL17A1, either through genetic overexpression or administration of Marimastat, a protease inhibitor, is sufficient to mitigate regenerative exhaustion. Consistently, in patient‐derived skin samples, COL17A1 levels correlate with ECM integrity and regenerative potential. Combined, a new stretch‐induced skin expansion model is established, revealing hidden components underlying regenerative exhaustion, and proposing Marimastat for drug repurposing. Restoration of COL17A1 is proposed to provide clinical benefits for skin expansion therapy.