Abstract
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.
Highlights
Glucocorticoid (GC) hormones regulate essential physiological functions including energy homeostasis, embryonic and postembryonic development, and the stress response [1,2,3,4]
Western blotting detection indicated that Gal-3 induced decreased expression of p16, p21, and p27 (Fig. 6B). These results suggest that interaction of Gal-3 and CD133 contributes to progenitor cells activation and loss of quiescence through the AMPactivated kinase (AMPK)/focal adhesion kinase (FAK) pathway
Our data demonstrate that elevated levels of Gal-3 signaling directed from aged niche leads to the loss of hepatic progenitor cells quiescence, which diminishes stemness and liver function in the long-term
Summary
Glucocorticoid (GC) hormones regulate essential physiological functions including energy homeostasis, embryonic and postembryonic development, and the stress response [1,2,3,4]. The mechanisms driving stress-induced changes of niche and progenitor cells remain unknown We address these questions in a dexamethasone (Dex)induced GC stress mice model. We examined the Dex-induced SASP and report that Galectin-3 (Gal-3), a kind of b-galactoside–binding lectin, elevated in Dex induced mice liver, is an aged niche factor, activates progenitor cells, and breaking its quiescence. We show that Gal-3 derived from the Dexinduced aged niche causes liver progenitor cells quiescence broken and long-term stemness exhaustion. Together these findings provide molecular insights into mechanisms linking stress and SASP to progenitor cell state and liver function, thereby pointing to biomarker and intervention possibilities
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