Modeling Familial MASH by iPSC-Hepatocytes

Area of Science:

• Hepatology
• Stem Cell Biology
• Genetics

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH) are increasing due to obesity.
• MASH can lead to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma.
• Current preclinical models, including cell lines and mouse models, do not accurately replicate human MASH pathogenesis.

Purpose of the Study:

• To develop a faithful preclinical platform for studying human genetic MASH.
• To characterize MASH pathogenesis using patient-derived induced hepatocytes (iHeps).

Main Methods:

• Identified families with genetic MASH predisposition.
• Reprogrammed patient skin fibroblasts into induced pluripotent stem cells (iPSCs).
• Differentiated iPSCs into hepatocytes (iHeps) for disease modeling and analysis of steatosis, apoptosis, mitochondrial function, and ER stress.

Main Results:

• MASH family iHeps exhibited increased baseline steatosis compared to control iHeps.
• Whole exome sequencing identified single nucleotide polymorphisms (SNPs) of unclear significance in MASH patients.
• Patients were heterozygous for the TM6SF2 E167K SNP, a finding explored in iHeps.

Conclusions:

• Human genetic MASH is complex.
• Patient-derived iHeps provide a powerful tool for characterizing complex human liver diseases like MASH.
• This study highlights the potential of iHeps for advancing MASH research and drug development.