Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

• DOI: 10.1007/s12072-019-10007-y
• Publication Date: 2019-12-13T08:37:41Z
• Authors: Gema Gómez-Mariano; Nerea Matamala; Selene Martínez; Iago Justo; Alberto Marcacuzco; Carlos Jimenez; Sara Monzón; Isabel Cuesta; Cristina Garfia; María Teresa Mart...; Meritxell Huch; Ignacio Pérez de ...; Manuel Posada; Sabina Janciauskiene; Beatriz Martínez-...
• Keywords: Organoid; Alpha 1-antitrypsin deficiency; Liver disease

Abstract Background and aims Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the gene, such as Z (Glu342Lys), results an expression misfolded AAT protein having high propensity to polymerize, accumulate hepatocytes thus enhance risk for hepatocyte damage subsequent liver disease. So far, relationship between Z-AAT accumulation cell remains not completely understood. We present three-dimensional organoid culture systems, novel tool modeling Z-AAT-related diseases. Methods have established organoids from biopsies patients with homozygous (ZZ) heterozygous (MZ) deficiency normal (MM) genotypes AAT. The features these models were characterized analyzing secretion intracellular aggregation MZ ZZ well differentiated cultures. Results Transcriptional analysis cultures RNA- Seq showed hepatocyte-specific profile. Genes, ALB, APOB, CYP3A4 , validated confirmed through quantitative-PCR analysis. cases lower protein, ALB APOB typically seen patients. Furthermore, responded external stimulus. Treatment oncostatin M, well-known inducer increased full-length transcripts (AAT-1C) short transcript (AAT-ST1C4). Conclusions Liver model recapitulates key provides useful disease modeling.