Stratifin Is Necessary for Spasmolytic Polypeptide-Expressing Metaplasia Development After Acute Gastric Injury.

BACKGROUND & AIMS: Chief cells can transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM), a metaplastic cell lineage, in response to acute injury after acid-secreting parietal cell loss in the stomach. Stratifin (SFN) acts as a multifunctional regulator, which can alter the function of multiple phosphoproteins. We have now examined how SFN contributes to the transdifferentiation of chief cells and the emergence of SPEM, as the initial metaplastic event in mucosal response to injury. METHODS: We performed single-cell RNA sequencing on transdifferentiating chief cells after a single dose of DMP-777 treatment to induce acute parietal cell atrophy in Mist1(CreERT2); LSL-tdTomato mice. We generated a Mist1(CreERT2); Sfn(flox/flox) mouse model to examine the effects of SFN loss in the transdifferentiation of chief cells and SPEM development in response to acute injury. Histologic examination and immunostaining were performed in the mouse stomachs to assess cell lineage marker expression. RESULTS: The single-cell RNA sequencing showed the initial characteristics of transdifferentiation of chief cells in response to acute injury. SFN expression was increased in transdifferentiating chief cells and SPEM cells. We determined that SFN loss in mice impairs the transdifferentiation of chief cells into SPEM following acute oxyntic atrophy in part by modulating EGFR/ERK signaling after acute injury. CONCLUSIONS: SFN is essential for the initiation of reprogramming of chief cells during transdifferentiation and SPEM development.