2026-06-14T00:31:55Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/91062025-06-17T13:31:17Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Gomez-Mariano, Gema Maria author Matamala, Nerea author Martinez Rodríguez, Selene author Justo, Iago author Marcacuzco, Alberto author Jimenez, Carlos author Monzon-Fernandez, Sara author Cuesta de la Plaza, Isabel author Garfia, Cristina author Varela Martinez, Maria del Carmen author Huch, Meritxell author Perez de Castro, Ignacio author Posada De la Paz, Manuel author Janciauskiene, Sabina author Martinez-Delgado, Beatriz author 2020-01 BACKGROUND AND AIMS: Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. METHODS: We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. RESULTS: Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). CONCLUSIONS: Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling. Hepatol Int. 2020 Jan;14(1):127-137. 10.1007/s12072-019-10007-y 1936-0541 1936-0533 Hepatology international 31832977 http://hdl.handle.net/20.500.12105/9106 Alpha-1 antitrypsin deficiency Liver Oncostatin M Organoids RNA-seq SERPINA1 Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease