Three-Dimensional Dynamic Cell Models for Metabolic Dysfunction-Associated Steatotic Liver Disease Progression

Area of Science:

• Hepatology and cell biology
• Biomedical engineering
• Disease modeling

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder involving steatosis, inflammation, and fibrosis.
• Current in vitro models struggle to replicate the multi-cellular complexity and allow for individual cell analysis.
• There is a need for advanced models that better represent MASLD stages and facilitate mechanistic studies.

Purpose of the Study:

• To develop and validate novel 3D dynamic coculture models for simulating MASLD progression.
• To enable the analysis of individual cell types within a complex liver microenvironment.
• To provide a platform for investigating MASLD pathogenesis and screening potential therapeutics.

Main Methods:

• Utilized a novel 3D hollow porous sphere cell carrier within a mini-bioreactor for dynamic culture.
• Established three distinct MASLD models: steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis, using specific cell ratios (hepatocytes, macrophages, hepatic stellate cells).
• Validated the 3D models using established MASLD mouse models fed a high-fat diet.

Main Results:

• The 3D models exhibited progressive hepatocyte viability decline and increased lipid accumulation, mirroring in vivo MASLD pathology.
• Gene expression profiles in the models correlated with those observed in MASLD-affected mouse livers.
• Comparative analysis revealed the significant role of pro-inflammatory macrophages in disrupting hepatocyte lipid metabolism.

Conclusions:

• The developed 3D dynamic coculture models provide a robust platform for studying MASLD mechanisms.
• These models facilitate the investigation of cell-specific contributions to MASLD progression.
• The platform shows promise for high-throughput screening of anti-MASLD therapeutic agents.