Suppressed Paracrine Signaling of Cystatin a from Keratinocytes to Fibroblasts and Endotheliocytes Delays Wound Healing in Diabetes

Impaired wound healing in diabetes involves disrupted communication between epidermal keratinocytes and dermal cells, yet the underlying regulatory factors remain incompletely understood. This study investigated the potential role of cystatin A (CSTA) in diabetic wound repair. CSTA expression was examined in high-glucose-treated keratinocytes and diabetic mouse skin. RNA sequencing and functional assays were performed to evaluate the effects of recombinant CSTA on human dermal fibroblasts and microvascular endothelial cells, while topical CSTA and calcipotriol were evaluated in diabetic C57BL/6J mouse wound models. CSTA expression was reduced under high-glucose and diabetic conditions. Recombinant CSTA enhanced fibroblast migration and proliferation-associated activity, promoted extracellular matrix-related gene expression, and improved endothelial migration and tube formation. Topical CSTA treatment accelerated wound closure, increased CD31-positive vascular structures, and enhanced collagen deposition in diabetic mice. Calcipotriol treatment similarly improved wound repair outcomes. These findings suggest that CSTA may contribute to the regulation of dermal repair processes and highlight its potential therapeutic relevance in diabetic wound healing, although the causal contribution of endogenous CSTA deficiency remains to be established.