Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.

中文翻译：

---

糖皮质激素应激诱导的分泌型半乳糖凝集素3引发肝祖细胞干性衰竭


成体祖细胞群通常在受控的生态位环境中以静止状态存在。然而，各种压力或形式的损伤可能会破坏这种状态，这通常会导致功能障碍和衰老。我们建立了糖皮质激素（GC）诱导的小鼠肝损伤模型，发现GC应激诱导肝损伤，导致祖细胞扩增。然而，生态位因子引起祖细胞增殖的机制在很大程度上尚不清楚。我们证明，在肝脏祖细胞生态位中，半乳糖凝集素 3 (Gal-3) 负责驱动祖细胞子集打破​​静止状态。我们发现 GC 应激会导致生态位老化，从而诱导 Gal-3 上调。增加的 Gal-3 群体越来越多地与祖细胞标记 CD133 相互作用，从而触发粘着斑激酶 (FAK)/AMP 激活激酶 (AMPK) 信号传导。这会导致静止状态的丧失，并导致祖细胞最终干性耗尽。相反，用抑制剂 TD139 阻断 Gal-3 可防止干性丧失并改善肝功能。这些实验确定了祖细胞生态位的压力依赖性变化，直接影响肝祖细胞的静止和功能。