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dc.contributor.authorGomez-Mariano, Gema Maria 
dc.contributor.authorMatamala, Nerea 
dc.contributor.authorMartinez Perez, Selene 
dc.contributor.authorJusto, Iago
dc.contributor.authorMarcacuzco, Alberto
dc.contributor.authorJimenez, Carlos
dc.contributor.authorMonzon-Fernandez, Sara 
dc.contributor.authorCuesta de la Plaza, Isabel 
dc.contributor.authorGarfia, Cristina
dc.contributor.authorVarela Martinez, Maria del Carmen 
dc.contributor.authorHuch, Meritxell
dc.contributor.authorPerez de Castro, Ignacio 
dc.contributor.authorPosada De la Paz, Manuel 
dc.contributor.authorJanciauskiene, Sabina
dc.contributor.authorMartinez-Delgado, Beatriz
dc.identifier.citationHepatol Int. 2020 Jan;14(1):127-137.es_ES
dc.description.abstractBACKGROUND 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.es_ES
dc.description.sponsorshipThis work was funded by grants from the Institute of Health Carlos III (AESI PI17CIII/00042 and DTS17CIII/00007) and Alpha-1 Antitrypsin Laurell’s Training award, ALTA 2017. Supporting institutions had no involvement in the study design; collection, analysis and interpretation of data; writing of the manuscript; and decision to submit the manuscript for publication.es_ES
dc.publisherSpringer es_ES
dc.subjectAlpha-1 antitrypsin deficiencyes_ES
dc.subjectOncostatin Mes_ES
dc.titleLiver organoids reproduce alpha-1 antitrypsin deficiency-related liver diseasees_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderInstituto de Salud Carlos III 
dc.identifier.journalHepatology internationales_ES
dc.repisalud.centroISCIII::Instituto de Investigación de Enfermedades Rarases_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/AESI PI17CIII/00042es_ES
dc.rights.accessRightsopen accesses_ES

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