ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program.

Differentiated cells across multiple species and organs can re-enter the cell cycle to aid in injury-induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive-enzyme-secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3-/- mice fail to induce RAB7-positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.

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

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.