Scientists develop first liver cell lines from HAE patients
Models provide platform for studies, treatment testing
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Researchers for the first time have developed separate liver cell lines, each derived from people with hereditary angioedema (HAE), that accurately replicate the molecular and cellular processes underlying the condition.
“These models not only exhibit key molecular features of HAE but also provide a versatile platform for mechanistic studies and preclinical drug testing,” the scientists wrote.
The study, “Hereditary Angioedema iPSC Models Implicate ER-Associated Degradation as a Potential Therapeutic Target,” was published in the Journal of Allergy and Clinical Immunology.
HAE is caused in nearly all cases by mutations in the SERPING1 gene, which encodes a protein called C1 esterase inhibitor (C1-INH). Most of these cases result in reduced C1-INH levels (type 1 HAE), while some involve normal levels but impaired C1-INH function (type 2 HAE). Low C1-INH levels lead to excessive bradykinin levels, a potent inflammatory mediator, triggering the swelling attacks that characterize the disease.
Lack of disease-specific model has been a challenge
A major challenge in HAE research is the lack of a stable, disease-specific cell model that accurately reflects what happens inside HAE patients’ cells.
The study detailed how researchers developed the first patient-derived induced pluripotent stem cell (iPSC) models of type 1 HAE. iPSCs are adult cells reprogrammed to become stem cells, which can then be directed to grow into many different cell types. Separate iPSC lines were generated from two HAE patients and named HAE102 and HAE201.
Genetic sequencing confirmed that each cell line retained the specific SERPING1 mutations found in the patients: HAE102 carried the p.Ala333Asp mutation, and HAE201 carried the p.Val492Glu mutation.
The scientists then stimulated the iPSCs to grow into hepatocyte-like cells, which resemble liver cells (hepatocytes), the primary site of C1-INH production in the body. By day 16, the cells had adopted a typical liver cell structure and expressed markers of liver cell identity.
When the HAE-derived cells were compared with cells from a healthy control iPSC line, scientists observed several differences. Although the total amount of C1-INH protein inside the cells was similar between the two cell types, the amount of C1-INH protein secreted into the surrounding culture medium was markedly lower in HAE cells. And SERPING1 gene expression (activity) was reduced by about half in the HAE lines.
The reduction in functional C1-INH was even more pronounced than the reduction in SERPING1 gene expression alone would predict. High-resolution microscopy revealed that C1-INH accumulated in clumps (aggregates) within HAE cells, specifically in the endoplasmic reticulum, the cellular structure responsible for protein folding and quality control.
Researchers then treated HAE cells with two androgen compounds: danazol, an approved HAE therapy, and dihydrotestosterone, to assess whether these could reduce C1-INH aggregation and improve its secretion. Danazol significantly increased mean C1-INH activity in HAE201’s cells, rising from 17.55% in untreated cells to 26.73%. Dihydrotestosterone also boosted C1-INH activity from 27.07% to 38.91%.
Under the microscope, researchers saw that both compounds reduced C1-INH aggregation and retention in the endoplasmic reticulum within patient-derived cells. Treatment did not affect SERPING1 gene expression, suggesting that the improvement in C1-INH activity occurred at the protein level rather than through increased gene activity.
“Patient-derived iPSC lines were successfully established and differentiated into [hepatocyte-like cells], providing a renewable and controllable platform to study HAE,” the researchers wrote. “The iPSC system enables mechanistic studies, preclinical drug testing, and exploration of gene therapy strategies in a patient-specific context.”
