Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells

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 glucocorticoids (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 cell 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 upregulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers FAK/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.

Elevated glucocorticoid alters the developmental dynamics of hypothalamic neurogenesis

“…In contrast to quiescent, apoptotic, or terminally differentiated cells, senescent cells have incurred an irreversible cell cycle arrest, yet remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression 38 . In support of our hypothesis, a previous study of liver progenitor cells reported that GC exposure induced cell proliferation leading to long-term replicative senescence/stemness exhaustion 39 , and GC is also reported to induce senescence of NSPCs (neural stem/progenitor cells) in vitro 40 . The presence of senescent cells in the proliferative zone of the GC-exposed hypothalamus at 13 dpf might explain why we observed reduced expression of pcna and rx3 , and a reduced proliferative capacity of the remaining glial cells in the proliferative zone of star:bPAC+ larvae.…”

The Therapeutic Potential of Galectin-3 in the Treatment of Intrahepatic Cholangiocarcinoma Patients and Those Compromised With COVID-19

“…Previous studies showed that the proliferation ability of cancer cells was significantly reduced after knockdown of Gal-3 in various cancer types ( Lalancette-Hebert et al, 2012 ; Ajani et al, 2018 ; Yang et al, 2020 ). Our data also demonstrated that inhibition of Gal-3 dramatically suppressed the proliferation and differentiation ability of ICC HCCC9810 cells as evidenced by increased cell ploidy time.…”

Possible value of galectin‐3 on follow‐up of cardiac remodeling during glucocorticoid treatment

“…Indeed, it has been clearly shown that 15 days of dexamethasone treatment causes many cardiovascular abnormalities, such as increased blood pressure, cardiac fibrosis, and cardiomyocyte apoptosis. [41] Besides, in a recent study, Yang et al [58] showed that 10-day of dexamethasone treatment (25 mg/kg per day) resulted in significantly increased blood glucose and decreased liver weight. Gal-3 gene expression in mice liver was also increased compared to the control group.…”