Timed Epithelial Overlay Preserves Defect Closure While Suppressing Fibrotic Remodeling in Wound Microtissues
Year: 2026
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Re-epithelialization restores barrier function and provides epithelial-derived paracrine signals that modulate fibroblast activation, contraction, and fibrotic remodeling. However, whether epithelial coverage can limit scar-like remodeling without compromising essential fibroblast-driven closure remains unclear. Here, we developed a tension-bearing NIH-3T3-collagen wound microtissue model supported by elastic scaffolds. A 500 μm circular microdefect was introduced to quantify epithelial regulation of closure dynamics and fibrotic remodeling. An MDCK epithelial overlay produced a strong, density-dependent inhibition of contraction-driven defect closure and suppressed the localized proliferative response at the wound edge. In contrast, delaying epithelial addition to 48 h postwounding preserved rapid closure while attenuating global microtissue compaction. This effect was partially mimicked by exogenous prostaglandin E 2, suggesting a role for soluble epithelial-derived signals. Delayed overlay maintained fibroblast repopulation of the healed region and enabled effective epithelial coverage of the regenerated surface. Moreover, delayed overlay markedly suppressed myofibroblast differentiation and fibronectin accumulation across the microtissue, attenuating radial remodeling gradients. Together, these findings identify an approximate postwounding epithelial loading window that preserves closure efficiency while limiting scar-like remodeling. This platform provides a quantitative framework for optimizing epithelial-assisted wound therapies and evaluating antifibrotic interventions in engineered 3D wound microenvironments.
Source: ACS Omega
Institution: Changzhou University
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,935
Awards: G6437398349, G6823513422
OpenAlex ID: W7155108630