2024-03-29T13:34:15Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/91062022-10-25T09:41:39Zcom_20.500.12105_2102com_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_2103
00925njm 22002777a 4500
dc
Gomez-Mariano, Gema Maria
author
Matamala, Nerea
author
Martinez RodrÃguez, 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.
1936-0533
http://hdl.handle.net/20.500.12105/9106
31832977
10.1007/s12072-019-10007-y
1936-0541
Hepatology international
Alpha-1 antitrypsin deficiency
Liver
Oncostatin M
Organoids
RNA-seq
SERPINA1
Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease