hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency

Charis-Patricia Segeritz, Sheikh Tamir Rashid, Miguel Cardoso de Brito, Maria Serra Paola, Adriana Ordonez, Carola Maria Morell, Joseph E. Kaserman, Pedro Madrigal, Nicholas Hannan, Laurent Gatto, Lu Tan, Andrew A. Wilson, Kathryn Lilley, Stefan J. Marciniak, Bibekbrata Gooptu, David A. Lomas, Ludovic Vallier

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)
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Background and Aims
α1-antitrypsin deficiency (A1ATD) is an autosomal recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant (Gly342Lys) retain polymerised protein in the endoplasmic reticulum (ER) of their hepatocytes, predisposing them to liver disease. The concomitant lack of circulating A1AT also causes lung emphysema. Greater insight into the mechanisms that link protein misfolding to liver injury will facilitate the design of novel therapies.

hiPSC-derived hepatocytes provide a novel approach to interrogate the molecular mechanisms of A1ATD because of their patient-specific genetic architecture and reflection of human physiology. To that end, we utilised patient-specific hiPSC hepatocytes (ZZ-HLCs) derived from an A1ATD (ZZ) patient, which faithfully recapitulated key aspects of the disease at the molecular and cellular level. Subsequent functional and “omics” comparisons of these cells with their genetically corrected isogenic-line (RR-HLCs) and primary hepatocytes/human tissue allowed the identification of new molecular markers and disease signatures.

Our studies showed that abnormal A1AT polymer processing (immobilized ER components, reduced luminal protein mobility and disrupted ER cisternae) occurred heterogeneously within hepatocyte populations and was associated with disrupted mitochondrial structure, presence of the oncogenic protein AKR1B10 and two upregulated molecular clusters centred on members of inflammatory (IL-18 and Caspase-4) and unfolded protein response (Calnexin and Calreticulin) pathways. These results were validated in a second patient-specific hiPSC line.

Our data identified novel pathways that potentially link the expression of Z A1AT polymers to liver disease. These findings could help pave the way towards identification of new therapeutic targets for treatment of A1ATD.

Lay Summary
This study compared the gene expression and protein profiles of healthy liver cells and those affected by the inherited disease α1-antitrypsin deficiency. This approach identified specific factors primarily present in diseased samples which could provide new targets for drug development. This study also demonstrates the interest of using hepatic cells generated from human induced pluripotent stem cells to model liver disease in vitro for uncovering new mechanisms with clinical relevance.
Original languageEnglish
Pages (from-to)851-860
JournalJournal of Hepatology
Issue number4
Early online date5 Jun 2018
Publication statusPublished - 1 Oct 2018


  • Hepatocyte
  • inherited liver disease
  • human induced pluripotent stem cell
  • α1-antitrypsin deficiency
  • inflammation


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