Liver sinusoidal endothelial TGF-β signaling accelerates partial endothelial-mesenchymal transition and MASH through...

Area of Science:

• Hepatology
• Endothelial Cell Biology
• Molecular Mechanisms of Disease

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern.
• Liver sinusoidal endothelial cells (LSECs) are key to liver health but their role in MASH is unclear.
• Understanding LSEC dysfunction in MASH is critical for developing new treatments.

Purpose of the Study:

• To investigate the specific role of LSECs in MASH progression.
• To identify the molecular mechanisms underlying LSEC dysfunction in MASH.
• To explore potential therapeutic targets within LSECs for MASH.

Main Methods:

• Single-cell RNA sequencing of MASH mouse livers.
• In vivo studies using LSEC-specific transgenic mouse models.
• In vitro experiments with primary LSECs and HUVECs.

Main Results:

• Identified a novel biphenotypic cell population in MASH livers originating from LSECs undergoing partial endothelial-mesenchymal transition (EndMT).
• Demonstrated that TGF-β signaling drives this partial EndMT in LSECs.
• Showed that TGF-β signaling activates Notch signaling in LSECs, promoting biphenotypic cell generation and MASH progression.
• Inhibition of TGF-β signaling attenuated MASH and suppressed LSEC partial EndMT.

Conclusions:

• A pathogenic TGF-β/Notch signaling axis drives MASH progression via LSEC partial EndMT.
• LSEC dysfunction is an active contributor to MASH pathogenesis.
• Targeting TGF-β signaling in LSECs presents a potential therapeutic strategy for MASH.