Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China.
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Cell Stem Cell. 2020 Jun 4;26(6):910-925.e6. doi: 10.1016/j.stem.2020.03.006. Epub 2020 Apr 2.
Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids. AMPK activation targets Krüppel-like factor 4 (KLF4), known to govern progenitor proliferation and PC fate choice, and PGC1α, which we show controls PC maturation after their specification. PC-specific deletion of AMPKα or PGC1α causes defective PC maturation, which could not be rescued by metformin. However, metformin treatment still increases KLF4 levels and suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitors to reduce self-renewal and promote PC fate, whereas AMPK-PGC1α activation within the PC lineage promotes maturation, providing a potential suggestion for why metformin increases acid secretion and reduces gastric cancer risk in humans.
细胞代谢在决定干细胞行为方面起着重要作用，尽管其在胃上皮稳态中的作用尚未得到深入评估。在这里，我们表明能量传感器 AMP 激酶 (AMPK) 控制胃上皮祖细胞的分化。在小鼠和类器官中，给予 AMPK 激活剂二甲双胍可减少上皮祖细胞的增殖并增加分泌胃酸的壁细胞 (PC)。AMPK 激活的靶标是 Krüppel 样因子 4 (KLF4)，已知其控制祖细胞的增殖和 PC 命运选择，以及 PGC1α，我们发现它控制着 PC 特化后的成熟。PC 特异性敲除 AMPKα 或 PGC1α 导致 PC 成熟缺陷，二甲双胍不能挽救这一缺陷。然而，二甲双胍治疗仍能增加 KLF4 水平并抑制祖细胞增殖。因此，AMPK 在祖细胞中激活 KLF4 以减少自我更新并促进 PC 命运，而 AMPK-PGC1α 在 PC 谱系中的激活则促进成熟，这为为什么二甲双胍能增加胃酸分泌并降低人类患胃癌的风险提供了潜在的解释。
