Modeling Hereditary Angioedema With Personalized Expanded Potential Stem Cell-Derived Hepatocytes: A CRISPR-Validated...

Area of Science:

• Genetics and Genomics
• Stem Cell Biology
• Human Disease Modeling

Background:

• Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency stems from SERPING1 mutations.
• Understanding mutation-specific mechanisms is hindered by a lack of relevant human models.

Purpose of the Study:

• To establish a personalized, stem cell-derived hepatocyte platform for investigating HAE pathophysiology.
• To analyze mutation-specific effects of SERPING1 variants on C1INH production.

Main Methods:

• Reprogramming patient peripheral blood mononuclear cell-derived erythroblasts into expanded potential stem cells (EPSCs).
• Differentiating EPSCs into hepatocyte-like cells (HLCs) for functional analysis.
• Utilizing CRISPR/Cas9 for genome repair and mutation introduction to confirm causality.

Main Results:

• Patient-derived HLCs showed impaired C1INH secretion with mutation-specific SERPING1 transcriptional and accumulation defects.
• CRISPR/Cas9 genome repair restored C1INH secretion, confirming the causal role of mutations.
• Engineered mutations in healthy cells replicated the HAE phenotype, validating the model's accuracy.

Conclusions:

• A robust, personalized hepatocyte model was established to study HAE.
• The model accurately recapitulates HAE pathophysiology and provides a platform for precision therapy research.