小柯机器人

美国华盛顿大学医学院Jason C. Mills课题组近日取得一项新成果。经过不懈努力，他们发现二甲双胍代谢通路调控胃祖细胞命运决定和成熟的不同阶段。这一研究成果于2020年4月2号在线发表在《细胞-干细胞》杂志上。

研究人员发现能量传感器AMP激酶（AMPK）调控胃上皮祖细胞的分化。在小鼠和类器官中，使用AMPK激活剂二甲双胍可减少上皮祖细胞增殖，并增加酸分泌性壁细胞（PC）。AMPK激活靶向Krüppel样因子4（KLF4）（已知其可控制祖细胞增殖和PC命运决定）和PGC1α（其特化后可控制PC成熟）。PC中AMPKα或PGC1α的特异性缺失会导致PC成熟缺陷，该缺陷无法通过二甲双胍挽救。

但是，二甲双胍治疗仍会增加KLF4水平并抑制祖细胞增殖。因此，AMPK激活祖细胞中的KLF4以减少自我更新并促进PC命运决定，而PC谱系中AMPK-PGC1α的激活则促进成熟，这暗示了二甲双胍为何会促进胃酸分泌并降低人患胃癌的风险。

据悉，细胞代谢在决定干细胞命运中起着重要作用，但是其在胃上皮稳态中的作用尚未得到深入研究。

附：英文原文

Title: A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation

Author: Zhi-Feng Miao, Mahliyah Adkins-Threats, Joseph R. Burclaff, Luciana H. Osaki, Jing-Xu Sun, Yan Kefalov, Zheng He, Zhen-Ning Wang, Jason C. Mills

Issue&Volume: 2020-04-02

Abstract: Cellular metabolism plays important functions in dictating stem cell behaviors, althoughits role in stomach epithelial homeostasis has not been evaluated in depth. Here,we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitordifferentiation. Administering the AMPK activator metformin decreases epithelial progenitorproliferation and increases acid-secreting parietal cells (PCs) in mice and organoids.AMPK activation targets Krüppel-like factor 4 (KLF4), known to govern progenitor proliferationand 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 couldnot be rescued by metformin. However, metformin treatment still increases KLF4 levelsand suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitorsto reduce self-renewal and promote PC fate, whereas AMPK-PGC1α activation within thePC lineage promotes maturation, providing a potential suggestion for why metforminincreases acid secretion and reduces gastric cancer risk in humans.

DOI: 10.1016/j.stem.2020.03.006

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30098-9

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