Regulation and Function of Sox2 and CD$_{44}$ Expression in the Stomach by Bone Morphogenetic Protein Signaling

Background and Aims
The transcription factor Sox2 and the adhesion molecule CD$_{44}$ are implicated in gastric metaplasia and neoplasia. Lgr5 is a cellular receptor that marks gastric progenitors involved in epithelial homeostasis. We reported that inhibition of bone morphogenetic protein (BMP) signaling in the stomach activates aberrant cells that lead to spasmolytic polypeptide-expressing metaplasia (SPEM), a preneoplastic metaplasia. We investigated the role of BMP-regulated transcriptional programs in gastric metaplasia/SPEM and the localization and function of CD$_{44}$ and Sox2 in the context of inhibition of BMP signaling.

Methods
Deletion of CD$_{44}$, Sox2, and of BMP Receptor 1a (Bmpr1a) in Lgr5 cells was achieved by crossing Lgr5-Cre mice to mice expressing floxed alleles of CD$_{44}$, Sox2, and Bmpr1a. The H$^+$/K$^+$-ATPase β-subunit promoter was used to express the BMP inhibitor noggin in the corpus. Lineage tracing studies were conducted by crossing Lgr5-Cre mice to mice expressing Nog and tdTomato. Morphology of the mucosa was analyzed by hematoxylin and eosin staining and immunohistochemistry. Single cell RNA sequencing was performed in both control and H$^+$/K$^+$-Nog mice.
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Results
Sox2$^{+ve}$ cells were detected in the antrum but not in the corpus/lesser curvature of wild type mice. Conversely, expression of Sox2 was seen in Lgr5$^{+ve}$ cells along the lesser curvature of Lgr5-Cre; Bmpr1a$^{flox/flox}$ mice and in CD$_{44}$$^{+ve}$ cells in the corpus of H$^+$/K$^+$-Nog mice. Noggin induced SPEM-signature genes in clusters expressing pit, chief, parietal, and mucus cell markers. Deletion of CD$_{44}$ and Sox2 in Lgr5 cells attenuated the SPEM phenotype.

Conclusion
Inhibition of BMP signaling affects gastric epithelial transcriptomes and cell plasticity, underscoring the relevance of this mechanism in the development of metaplasia and in the regulation of CD$_{44}$ and Sox2.