Background & Aims

Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified.

Methods

We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment).

Results

Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2⁺ isthmus progenitors, but not Hdc⁺ mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r⁺Hdc^- cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro.

Conclusions

We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R⁺ progenitors in the corpus. Gastrin-dependent function of CCK2R⁺ progenitors is regulated by the extracellular signal-regulated kinase pathway.

中文翻译：

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高胃泌素血症通过 ERK 激活通过 CCK2R+ 祖细胞扩展胃 ECL 细胞。

背景与目标

胃中的肠嗜铬样 (ECL) 细胞表达胃泌素/胆囊收缩素 2 受体 CCK2R，并且已知会在高胃泌素血症下扩增，但这是否是由于现有 ECL 细胞的扩增或祖细胞产量增加尚未阐明。

方法

我们使用在 ECL 细胞中表达绿色荧光蛋白荧光报告基因的小鼠（组氨酸脱羧酶 [Hdc]-绿色荧光蛋白），以及Cck2r和 Hdc 驱动的他莫昔芬诱导型重组酶 Cre（Cck2r-CreERT2、Hdc-CreERT2）小鼠与Rosa26Sor-tdTomato (R26-tdTomato) 小鼠，并通过使用高胃泌素血症模型（胃泌素输注、奥美拉唑治疗）研究了它们在胃体中的表达和细胞命运。

结果

HDc-GFP 标记了大多数 ECL 细胞，位于胃腺的下三分之一。高胃泌素血症导致 ECL 细胞扩张，不仅限于腺体基部，并促进胃峡部的细胞增殖 (Ki67)，但在基底 ECL 细胞中没有。Cck2r -CreERT2 小鼠标记了大多数 ECL 细胞，以及位于腺体较高位置的分散细胞类型，其数量在高胃泌素血症期间增加。Cck2r -CreERT2 ⁺峡部祖细胞，但不是 Hdc ⁺成熟 ECL 细胞，是高胃泌素血症期间 ECL 细胞增生的来源，并且可以在体外生长为 3 维球状体。此外，体外胃泌素处理促进了分选的Cck2r ⁺ Hdc球体的形成^-细胞，以及在 CCK2R 衍生的类器官中增加的嗜铬粒蛋白 A 和磷酸化的细胞外信号调节激酶表达。胃泌素在体内和体外激活细胞外信号调节激酶通路，用丝裂原活化蛋白激酶激酶 1 抑制剂 U0126 治疗可阻断高胃泌素血症介导的变化，包括体内 CCK2R 衍生的 ECL 细胞增生以及球体形成和嗜铬粒蛋白 A体外表达。

结论

我们在此表明​​，高胃泌素血症诱导 ​​ECL 细胞增生，这主要来源于语料库中的CCK2R ^{+祖细胞。CCK2R +}祖细胞的胃泌素依赖性功能受细胞外信号调节激酶途径的调节。