Abstract
Wound healing restores tissue integrity through tightly coordinated cellular and molecular programs, yet the biological processes that persist after apparent closure remain largely unexplored. Using a standardized mouse hard palate injury model combined with histological, lineage-tracing, molecular, and epigenetic analyses, we show that rapid re-epithelialization is followed by months of cellular remodeling. Although wounds re-epithelialized within two weeks, temporal analyses revealed that the regenerated epithelium maintained leading-edge-like features for months. Structural reorganization, including increased cell density and epithelial thickness, persisted well beyond closure, accompanied by sustained proliferation and elevated apoptosis mediated by the p53-p21 pathway, thereby removing cells with DNA damage during tissue remodeling. Lineage tracing revealed marked alterations in Wnt-responsive epithelial stem cells, which were transiently lost from the repaired epithelium and gradually repopulated the tissue over approximately four months. Repair-activated keratinocytes showed sustained expression of keratin 6 and keratin 17 and delayed recovery of differentiation markers keratin 10 and filaggrin, indicating prolonged epithelial activation despite morphological closure. Coordinated alterations in histone marks H2AK119ub, H3K27ac, and H3K27me3, and persistent immune infiltration, indicate lasting molecular and microenvironmental remodeling that maintains the tissue in a memory-like state. Together, these findings indicate that oral wound healing is an extended, multi-phase process in which post-healing remodeling restores epithelial homeostasis and ensures proper resolution of the repair response.
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This work was supported by the National Institute of Dental and Craniofacial Research (R00DE028585 and R03DE033059 to X. Y.), Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (to X.Y.), and the Ralph W. and Grace M. Showalter Research Trust (to X.Y.).
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All animal experimental protocols were performed in accordance with the relevant guidelines and regulations and were approved by the Indiana University Institutional Animal Care and Use Committee (IACUC, protocol #24012). This study did not involve human participants; therefore, informed consent was not applicable.
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Walton, C.J., Thompson, T., Syed, S.A. et al. Beyond re-epithelialization: prolonged remodeling re-establishes epithelial homeostasis in oral mucosa. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08804-z
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DOI: https://doi.org/10.1038/s41419-026-08804-z
