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Immediate but Temporal Response: The Role of Distal Epithelial Cells in Wound Healing

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Abstract

Efficient oral mucosal wound healing requires coordinated responses from epithelial progenitor cells, yet their spatiotemporal recruitment and activation remain unclear. Using a mouse model of palatal mucosal wound healing, we investigated the dynamics of epithelial cells during this process. Proliferation analysis revealed that, in addition to the expected proliferation center near the wound edge, distal cell populations rapidly activated post-injury by elevating their mitotic activity. These distal cells displayed predominant lateral expansion in the basal layer, suggesting roles beyond just tissue renewal. However, while proximal proliferation center cells sustained heightened proliferation until re-epithelialization was completed, distal cells restored basal turnover rates before wound closure, indicating temporally confined contributions. Lineage tracing of Wnt-responsive epithelial cells showed remarkable clone expansion in basal layers both proximally and distally after wounding, contrasting with gradual clone expansion in homeostasis. Although prioritizing tissue repair, epithelial progenitor cells maintained differentiation programs and barrier functions, with the exception of the leading edge. At the leading edge, we found accelerated cell turnover, but the differentiation program was suspended. In summary, our findings uncovered that oral wound re-epithelialization involves two phases: an initial widespread response with proliferation of proximal and distal cells, followed by proliferation confined to the wound proximal region. Uncovering these stage-specific healing mechanisms provides insights for developing targeted therapeutic strategies to improve wound care.

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Data Availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary file. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Otolaryngology-Head & Neck Surgery, School of Medicine, Indiana University, Indianapolis, IN, USA

    Tyler Thompson, Shannan Flanagan, Dayane Ortega-Gonzalez & Xue Yuan

  2. Department of Biomedical Sciences and Comprehensive Care, School of Dentistry, Indiana University, Indianapolis, IN, USA

    Tianli Zhu

  3. Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Xue Yuan

  4. Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN, USA

    Xue Yuan

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Contributions

T.T., S.F., D.O., T.Z.: Contributed to data acquisition and interpretation, performed statistical analyses, and drafted and critically revised the manuscript. X.Y.: Contributed to the conception and design of the research, data acquisition, data interpretation, and drafted and critically revised the manuscript. All authors gave their final approval and agreed to be accountable for all aspects of the work.

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Correspondence to Xue Yuan.

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Thompson, T., Flanagan, S., Ortega-Gonzalez, D. et al. Immediate but Temporal Response: The Role of Distal Epithelial Cells in Wound Healing. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10734-2

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