Zonated mechanosensing by PIEZO1 controls liver regeneration

Area of Science:

• Hepatology and regenerative medicine
• Mechanobiology
• Molecular and cellular biology

Background:

• The liver's remarkable regenerative capacity is organized into distinct zones.
• The precise mechanisms by which tissue mechanics coordinate zonated hepatocyte proliferation during regeneration are not well understood.

Purpose of the Study:

• To investigate the role of mechanical cues in liver regeneration.
• To identify the specific cell populations and molecular pathways involved in mechanosensing during liver regrowth.

Main Methods:

• Utilized mouse models to study liver regeneration.
• Employed genetic manipulation of PIEZO1 and dipeptidyl peptidase-4 (DPP4) expression.
• Investigated the expression of DPP4 and PIEZO1 in different hepatocyte subpopulations.
• Assessed the impact of PIEZO1 modulation on hepatocyte proliferation and liver regrowth.

Main Results:

• Identified a subpopulation of mid-lobular hepatocytes, characterized by DPP4 expression, as the key proliferative pool.
• Demonstrated that PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4+ hepatocytes.
• Showed that PIEZO1 integrates biomechanical cues to drive liver regrowth via insulin-like growth factor binding protein 2 (IGFBP2).
• Found that genetic disruption of PIEZO1 impairs hepatocyte proliferation and liver regeneration.
• Observed that enhanced PIEZO1 function accelerates liver recovery.

Conclusions:

• DPP4+ mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing.
• Established a direct link between tissue mechanics and liver regeneration.
• Highlighted the region-specific contribution of mechanical cues to liver repair.