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. 2021 Dec;66(12):4263-4273.
doi: 10.1007/s10620-020-06756-8. Epub 2021 Jan 19.

P63 Deficiency and CDX2 Overexpression Lead to Barrett's-Like Metaplasia in Mouse Esophageal Epithelium

Yu Fang #  1   2 , Wenbo Li #  3   2 , Xiaoxin Chen  4
Affiliations

P63 Deficiency and CDX2 Overexpression Lead to Barrett's-Like Metaplasia in Mouse Esophageal Epithelium

Yu Fang et al. Dig Dis Sci. 2021 Dec.

Abstract

Background: The cellular origin and molecular mechanisms of Barrett's esophagus (BE) are still controversial. Trans-differentiation is a mechanism characterized by activation of the intestinal differentiation program and inactivation of the squamous differentiation program.

Aims: Renal capsule grafting (RCG) was used to elucidate whether CDX2 overexpression on the basis of P63 deficiency in the esophageal epithelium may generate intestinal metaplasia.

Methods: P63-/-;Villin-Cdx2 embryos were generated by crossing P63+/- mice with Villin-Cdx2 mice. E18.5 esophagus was xenografted in a renal capsule grafting (RCG) model. At 1, 2, or 4 weeks after RCG, the mouse esophagus was immunostained for a proliferation marker (BrdU), squamous transcription factors (SOX2, PAX9), squamous differentiation markers (CK5, CK4, and CK1), intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6), intestinal columnar epithelial cell markers (A33, CK8), goblet cell marker (MUC2, TFF3), Paneth cell markers (LYZ and SOX9), enteroendocrine cell marker (CHA), and Tuft cell marker (DCAMKL1).

Results: The P63-/-;Villin-Cdx2 RCG esophagus was lined with proliferating PAS/AB+ cuboidal cells and formed an intestinal crypt-like structure. The goblet cell markers (TFF3 and MUC2) and intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6) were expressed although no typical morphology of goblet cells was observed. Other intestinal cell markers including enteroendocrine cell marker (CHA), Paneth cell markers (LYZ and Sox9), and intestinal secretory cell marker (UEA/WGA) were also expressed in the P63-/-;Villin-Cdx2 RCG esophagus. Squamous cell markers (PAX9 and SOX2) were also expressed, suggesting a transitional phenotype.

Conclusion: CDX2 overexpression on the basis of P63 deficiency in esophageal epithelial cells induces Barrett's-like metaplasia in vivo. Additional factors may be needed to drive this transitional phenotype into full-blown BE.

Keywords: Barrett’s esophagus; CDX2; Esophagus; P63; Renal capsule grafting.

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Conflict of interest statement

Disclosure of potential conflicts of interest: The authors have no conflict of interest to declare.

Figures

Figure 1.
Figure 1.
Morphology (gross view and H&E staining), proliferation (BrdU) and expression of differentiation markers (CK5, CK4, and CK1) in wild-type esophageal epithelium at 1, 2 and 4 weeks after RCG. Scale bar=1mm (A to C), or 50μm (D to R).
Figure 2.
Figure 2.
Expression of P63, CDX2, and VIL in the esophageal epithelial cells of wild-type, P63−/− and P63−/−;Villin-Cdx2 mice (E18.5). Scale=50μm.
Figure 3.
Figure 3.
Morphology (gross view and H&E staining) and PAS/AB staining of P63−/− and P63−/−;Villin-Cdx2 RCG esophagus at 1, 2 or 4 weeks. Red arrows indicate the esophagus under renal capsule. Panel B’, E’, H’, K’, O’, R’ are enlarged parts of Panel B, E, H, K, O, R. Panel C’, F’, I’ M’, P’, S’ are enlarged parts of Panel C, F, I, M, P, S. Scale bar=50μm.
Figure 4.
Figure 4.
Expression of P63, VIL, CDX2, proliferation marker (BrdU), goblet cell markers (TFF3, MUC2), and intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, GATA6) in P63−/−;Villin-Cdx2 RCG esophagus at Week 4. Scale bar=50μm.
Figure 5.
Figure 5.
Expression of secretory cell marker (UEA1/WGA), enteroendocrine cell maker (CHA), Paneth cell markers (SOX9, LYZ), Tuft cell marker (DCAMKL1), intestinal columnar cell markers (A33, CK8), and squamous epithelial cell marker (PAX9, SOX2) in P63−/− and P63−/−;Villin-Cdx2 RCG esophagus at Week 4. Scale bar=50μm.
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