(W1107) RECAPITULATING HEREDITARY ANGIOEDEMA USING A PERSONALIZED EXPANDED POTENTIAL STEM CELL (EPSC) PLATFORM: DEMONSTRATING SIGNALS OF LIVER DISEASE AMONG HEPATOCYTES DIFFERENTIATED FROM PATIENT EPSC
Abstract: Hereditary angioedema (HAE) is mostly caused by deficiency or dysfunction of C1-esterase inhibitor (C1-INH), caused by the mutations of SERPING1 – which is predominantly expressed in hepatocytes. The exact pathomechanism of SERPING1 mutations has not been fully elucidated, and previous studies have primarily focused only on circulating C1-INH. Evidence showed HAE to be more of a metabolic liver disorder, but studies on patient hepatocytes have been limited by difficulty in acquiring relevant samples. In this study, we utilized our expanded stem cell (EPSC) platform to derive hepatocytes from individual HAE patients with different type I or type II HAE mutations. Using this personalized disease model, we found patient EPSCs showed comparable pluripotency and trilineage differentiation capability as healthy controls. All EPSCs could be further differentiated into hepatocytes which showed typical polygonal and binuclear hepatic characteristics and expressed critical hepatocyte markers. However, patient EPSC-derived hepatocytes showed morphological abnormalities compared to controls, including ballooning, displaced nuclei, lipid deposition, and other apoptosis-like features. Hepatocytes from type I HAE patients demonstrated < 50% expression of SERPING1 at both RNA and protein levels, while those from type II HAE patients showed equal expression, compared to controls. Furthermore, patient-derived hepatocytes demonstrated retention of C1-INH within the cytoplasm, significantly more in type II than type I patients. Moreover, bulk RNA sequencing showed that patient-derived hepatocytes significantly upregulate collagen-containing extracellular matrix and ZFP41, common hallmarks of chronic liver disease and hepatocellular carcinoma. At last, repaired patient_EPSC-derived hepatocytes showed normalized expression and secretion of SERPING1 together with a decrease of ZFP41 and amelioration of fibrosis. In conclusion, our patient EPSC-derived hepatocytes were able to accurately model SERPING1 dysfunction and we confirmed that HAE is indeed a metabolic liver disorder – with hepatocytes demonstrating retention of C1-INH in their cytoplasm and expression of markers typical of chronic liver disease. Furthermore, we showed the possibility of curing the disease by genetic editing.
