Application of IFN-γ-Licensed urine-derived stem cells in SIS hydrogel promotes scar-free wound healing by immunomodulation and microenvironment remodeling.

Abstract

Scar-free wound healing remains an unmet clinical imperative, as dysregulated immune microenvironment during tissue repair drives irreversible fibrosis. While existing treatments (corticosteroid injections, laser therapy, surgical excision) provide symptomatic relief, they fail to address the pathophysiological triad of fibrosis: persistent fibroblast activation, aberrant ECM deposition, and chronic inflammation. Mesenchymal stem cell (MSC) therapy has emerged as a promising strategy to concurrently target these pathological axes. Among MSC sources, urine-derived stem cells (USCs) stand out as a superior candidate, owing to their non-invasive accessibility, minimal ethical concerns, favorable safety profile, and robust proliferative capacity. In this study, we explored the therapeutic potential of IFN-γ-pretreated urine-derived stem cells (γ-USCs) encapsulated in small intestinal submucosa (SIS) hydrogel for scar-free skin wound healing. Our findings demonstrated that IFN-γ pretreatment potentiated the immunomodulatory properties of USCs, driving macrophage polarization toward an anti-inflammatory phenotype to normalize the wound microenvironment. In vitro, γ-USCs significantly suppressed the hyperactivity of keloid fibroblasts and attenuated TGF-β-induced fibrotic responses, as evidenced by reduced collagen deposition and downregulated fibrotic markers. In vivo, using a rabbit ear scar model, SIS hydrogel-encapsulated γ-USCs (γ-USCs@SIS) markedly alleviated scar formation, with histopathological analyses revealing improved tissue architecture, balanced collagen remodeling, and restored skin biological function. Collectively, the γ-USCs@SIS system synergizes the enhanced immunomodulatory capacity of IFN-γ-pretreated USCs with the supportive microenvironment provided by SIS hydrogel, offering an innovative and translatable strategy for scar-free wound healing. This approach holds significant potential to advance fibrosis treatment by addressing the root causes of pathological scarring.