Caldwell B,Gut. 2022 Jun;71(6):1068-1077. 

化生源于不同类型的细胞对损伤的反应，被认为是许多癌症的前兆。异种细胞系存在于对损伤做出反应的修复性化生粘膜中，包括小孔细胞、增殖细胞和关键的化生细胞群——痉挛松解多肽表达化生(SPEM)细胞。分泌酶原的主细胞是胃黏膜中长期存活的细胞，被认为是SPEM细胞的起源;然而，一种相互矛盾的范式提出峡部祖细胞是SPEM的起源

胃内因子(Gastric intrinsic factor, GIF)是一种胃组织特异性基因，具有成熟小鼠主细胞所特有的蛋白表达。研究生成一个新的主要细胞特异性驱动小鼠等位基因GIF-rtTA。采用GIF-GFP报告小鼠验证GIF-rtTA驱动因子在主细胞中的特异性。使用GIF-Cre-RnTnG小鼠在稳态和急性化生发育过程中进行谱系追踪。采用L635诱导急性黏膜损伤，并对胃系标志物进行免疫荧光共染色

在急性黏膜损伤后的化生过程中，成熟的主细胞而不是峡部祖细胞是SPEM细胞的主要来源。此外，在主细胞中的GFP标记后 1 年观察到长期保留标记的主细胞。然而，只有一小部分长期保留标签的主细胞表现出在稳态中的重编程能力。相比之下，确定主要细胞起源的SPEM细胞有助于响应急性黏膜损伤的中央凹细胞增生中的谱系

ABSTRACT

Objective Metaplasia arises from differentiated cell types in response to injury and is considered a precursor 

in many cancers. Heterogeneous cell lineages are present in the reparative metaplastic mucosa with response to injury, including foveolar cells, proliferating cells and spasmolytic polypeptide-expressing metaplasia (SPEM) 

cells, a key metaplastic cell population. Zymogen_x0002_secreting chief cells are long-lived cells in the stomach 

mucosa and have been considered the origin of SPEM cells; however, a conflicting paradigm has proposed 

isthmal progenitor cells as an origin for SPEM.Design Gastric intrinsic factor (GIF) is a stomach tissue_x0002_specific gene and exhibits protein expression uniquet mature mouse chief cells. We generated a novel chief cell-specific driver mouse allele, GIF-rtTA. GIF-GFP reporter mice were used to validate specificity of GIF-rtTA driver in chief cells. GIF-Cre-RnTnG mice were used to perform lineage tracing during homoeostasis and acute metaplasia development. L635 treatment was used to induce acute mucosal injury and coimmunofluorescence 

staining was performed for various gastric lineage markers.

Results We demonstrated that mature chief cells, rather than isthmal progenitor cells, serve as the predominant origin of SPEM cells during the metaplastic process after acute mucosal injury. Furthermore, we observed long_x0002_term label-retaining chief cells at 1 year after the GFP labelling in chief cells. However, only a very small subset of the long-term label-retaining chief cells displayed the reprogramming ability in homoeostasis. In contrast, we identified chief cell-originating SPEM cells as contributing to lineages within foveolar cell hyperplasia in response to the acute mucosal injury.

Conclusion Our study provides pivotal evidence for cell plasticity and lineage contributions from differentiated gastric chief cells during acute metaplasia development.

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