A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation
| Autor: | Yan Kefalov, Jing Xu Sun, Joseph Burclaff, Zheng He, Zhi Feng Miao, Jason C. Mills, Zhenning Wang, Luciana H. Osaki, Mahliyah Adkins-Threats |
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| Rok vydání: | 2019 |
| Předmět: |
mTORC1
Biology AMP-Activated Protein Kinases Article 03 medical and health sciences Kruppel-Like Factor 4 Mice 0302 clinical medicine Genetics medicine Animals Progenitor cell 030304 developmental biology Progenitor 0303 health sciences Activator (genetics) Stem Cells Stomach AMPK Cell Biology Metformin Cell biology KLF4 Molecular Medicine Stem cell 030217 neurology & neurosurgery Metabolic Networks and Pathways medicine.drug |
| Zdroj: | Cell Stem Cell |
| ISSN: | 1875-9777 |
| Popis: | 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 Kruppel-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. |
| Databáze: | OpenAIRE |
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