Poly-L-Lactic Acid Attenuates Fibrotic Remodeling During Cutaneous Wound Healing

Pathological hypoxia following cutaneous injury is a critical driver of wound chronicity and fibrotic remodeling. The nuclear receptor binding SET domain protein 2 (NSD2)/lysine demethylase 2A (KDM2A)–histone H3 lysine 36 dimethylation (H3K36me2) axis is a known regulator of hypoxia-induced epithelial-to-mesenchymal transition (EMT) in malignancy; however, its role in skin repair remains largely unexplored. We investigated whether poly-L-lactic acid (PLLA) could attenuate fibrotic remodeling by modulating the NSD2/KDM2A–H3K36me2 axis and examining angiogenic signaling. We used a murine 9 mm punch-wound model for in vivo assessment and HaCaT keratinocytes and human dermal fibroblasts (HDFs) exposed to 2% O2 as in vitro hypoxia models. PLLA was administered to evaluate its impact on angiogenic signaling, collagen architecture, and the NSD2/KDM2A pathway. PLLA was associated with increased angiogenic markers and reduced expression of several hypoxia-associated epigenetic and fibrotic markers. In mice, PLLA increased vascular endothelial growth factor (VEGF)/VEGF receptor 2 expression and blood vessel abundance. In addition, PLLA decreased NSD2 and H3K36me2 levels while increasing KDM2A levels. Histological analysis showed less dense collagen staining and a change in the collagen type I/type III staining ratio, alongside a smaller photographically defined residual lesion area. Under controlled hypoxic conditions in vitro, PLLA suppressed EMT-related transcription factors, including Snail, Slug, and Twist, in keratinocytes and attenuated transforming growth factor-β1/phosphorylated mothers against decapentaplegic homolog 2/3 signaling and α-smooth muscle actin expression in fibroblasts. These findings support further study of PLLA-associated changes in vascular, epithelial, and fibrotic markers during wound remodeling.