Irx1 mechanisms for oral epithelial basal stem cell plasticity during reepithelialization after injury
Dan Su, … , Steven Eliason, Brad A. Amendt
Dan Su, … , Steven Eliason, Brad A. Amendt
Published January 9, 2025
Citation Information: JCI Insight. 2025;10(1):e179815. https://doi.org/10.1172/jci.insight.179815.
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Research Article Cell biology Stem cells

Irx1 mechanisms for oral epithelial basal stem cell plasticity during reepithelialization after injury

Abstract

The oral mucosa undergoes daily insults, and stem cells in the epithelial basal cell layer regenerate gingiva tissue to maintain oral health. The Iroquois Homeobox 1 (IRX1) protein is expressed in the stem cell niches in human/mouse oral epithelium and mesenchyme under homeostasis. We found that Irx1+/– heterozygous (Het) mice have delayed wound closure, delayed morphological changes of regenerated epithelium, and defective keratinocyte proliferation and differentiation during wound healing. RNA-Seq analyses between WT and Irx1+/– mice at 3 days postinjury (dpi) found impaired epithelial migration and decreased keratinocyte-related genes upon injury. IRX1-expressing cells are found in the gingival epithelial basal cell layer, a stem cell niche for gingival maintenance. IRX1-expressing cells are also found in cell niches in the underlying stroma. IRX1 activates SOX9 in the transient amplifying layer to increase cell proliferation, and EGF signaling is activated to induce cell migration. Krt14CreERT lineage tracing experiments reveal defects in the stratification of the Irx1+/– HET mouse oral epithelium. IRX1 is primed at the base of the gingiva in the basal cell layer of the oral epithelium, facilitating rapid and scarless wound healing through activating SOX9 and the EGF signaling pathway.

Authors

Dan Su, Tadkamol Krongbaramee, Samuel Swearson, Yan Sweat, Mason Sweat, Fan Shao, Steven Eliason, Brad A. Amendt

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Figure 6

The regenerated epithelium of Irx1+/– mice showed prolonged high SOX2 and KRT6 expression at 3 dpi.

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The regenerated epithelium of Irx1+/– mice showed prolonged high SOX2 an...
(A–D) Representative IF staining images of SOX2 in control and injured gingival tissue of Irx1+/+ and Irx1+/– mice at 3 dpi. (A) SOX2 expression was assessed in the Irx1+/+ control gingiva. SOX2 marked the basal and spinous layer. (B) SOX2 expression was assessed in the regenerated epithelium in Irx1+/+ at 3 dpi. (C) SOX2 expression was assessed in the Irx1+/– control gingiva. SOX2 marked the basal and spinous layer. (D) SOX2 expression was assessed in the regenerated epithelium in Irx1+/– at 3 dpi. The regenerative front is ~600 μm to the first molar. (E–H) Representative IF staining images of SOX2 and Keratin 6A in control and injured gingival tissue of Irx1+/+ and Irx1+/– mice at 3 dpi. (E) KRT6A expression was assessed in the Irx1+/+ control gingiva and costained with SOX2. KRT6A marks the JE and spinous and granular keratinocytes. (F) KRT6A expression was assessed in the regenerated epithelium in Irx1+/+ at 3 dpi and costained with SOX2. (G) KRT6A expression was assessed in the Irx1+/– control gingiva and costained with SOX2. KRT6A marks the JE and spinous and granular keratinocytes. (H) KRT6A expression was assessed in the regenerated epithelium in Irx1+/– at 3 dpi and costained with SOX2. The regenerative front is ~600 μm to the first molar. Blue staining represents nuclei. White dashed lines demarcate the gingival epithelium and mesenchyme. Image area covers the region of injury. Scale bar: 100 μm. RF, regenerative front; T, tooth; JE, junctional epithelium.