Won Yoonkyung, Sohn Yoojin, Lee Su-Hyung, Goldstein Anna, Gangula Rama, Mallal Simon, Goldenring James R
Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
Cell Mol Gastroenterol Hepatol. 2025 Apr 23;19(8):101521. doi: 10.1016/j.jcmgh.2025.101521.
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.
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; LSL-tdTomato mice. We generated a Mist1; Sfn 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.
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.
SFN is essential for the initiation of reprogramming of chief cells during transdifferentiation and SPEM development.
胃中泌酸壁细胞丢失后，主细胞可因急性损伤而转分化为表达解痉多肽的化生（SPEM）细胞系，这是一种化生细胞谱系。层粘连蛋白（SFN）作为一种多功能调节因子，可改变多种磷酸化蛋白的功能。我们现在研究了SFN如何促进主细胞的转分化以及SPEM的出现，这是黏膜对损伤反应中的初始化生事件。
我们对经单剂量DMP - 777处理诱导Mist1；LSL - tdTomato小鼠急性壁细胞萎缩后的转分化主细胞进行了单细胞RNA测序。我们构建了Mist1；Sfn小鼠模型，以研究SFN缺失对主细胞转分化和急性损伤后SPEM发育的影响。对小鼠胃进行组织学检查和免疫染色，以评估细胞谱系标志物的表达。
单细胞RNA测序显示了主细胞对急性损伤转分化的初始特征。在转分化的主细胞和SPEM细胞中，SFN表达增加。我们确定，小鼠中SFN的缺失部分通过调节急性损伤后的EGFR/ERK信号传导，损害了急性胃体萎缩后主细胞向SPEM的转分化。
SFN对于主细胞在转分化和SPEM发育过程中重编程的启动至关重要。
