Cellular senescence primes liver fibrosis regression through Notch-EZH2

Area of Science:

• Hepatology
• Cellular Biology
• Immunology

Background:

• Cellular senescence is increasingly recognized for its role in tissue repair and regeneration.
• Liver fibrosis regression involves complex cellular dynamics, including the presence of senescent cells.

Purpose of the Study:

• To investigate the role of senescent cells in liver fibrosis regression.
• To elucidate the molecular mechanisms, including the Notch-EZH2 pathway, regulating senescent cells during fibrosis regression.

Main Methods:

• Flow cytometry and single-cell RNA sequencing to identify senescent cell populations.
• Pharmacological interventions (dasatinib, quercetin, EPZ6438, Ly3039478) and genetic models (Lyz2-Cre-RBP-J mice) to manipulate senescence and signaling pathways.
• Macrophage depletion using clodronate.

Main Results:

• Senescent nonparenchymal liver cells accumulate during fibrosis regression.
• Eliminating senescent cells or macrophages impeded fibrosis regression.
• The Notch-Hes1 pathway epigenetically regulates enhancer of zeste homolog 2 (EZH2), influencing senescent cell numbers and fibrosis regression.
• Modulating Notch signaling or EZH2 activity impacted senescent cell populations and fibrosis resolution.

Conclusions:

• Senescent cells, particularly liver nonparenchymal cells and macrophages, are essential for effective liver fibrosis regression.
• The Notch-EZH2 signaling axis is a key regulator of senescent cell dynamics during fibrosis resolution.
• Targeting senescent cells or the Notch-EZH2 pathway presents a potential therapeutic strategy for liver fibrosis.