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hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in ?1-antitrypsin deficiency

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


Charis-Patricia Segeritz

Sheikh Tamir Rashid

Miguel Cardoso de Brito

Maria Paola Serra

Adriana Ordonez

Carola Maria Morell

Joseph E. Kaserman

Pedro Madrigal

Laurent Gatto

Lu Tan

Andrew A. Wilson

Kathryn Lilley

Stefan J. Marciniak

Bibek Gooptu

David A. Lomas

Ludovic Vallier


© 2018 The Authors Background & 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. Methods: Human-induced pluripotent stem cell (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 hepatocyte-like cells (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 enabled identification of new molecular markers and disease signatures. Results: Our studies showed that abnormal A1AT polymer processing (immobilised 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. Conclusions: 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 the 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.


Segeritz, C., Rashid, S. T., de Brito, M. C., Serra, M. P., Ordonez, A., Morell, C. M., …Vallier, L. (2018). hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency. Journal of Hepatology, 69(4), 851-860.

Journal Article Type Article
Acceptance Date May 17, 2018
Online Publication Date Jun 5, 2018
Publication Date Oct 1, 2018
Deposit Date Dec 5, 2018
Publicly Available Date Dec 6, 2018
Journal Journal of Hepatology
Print ISSN 0168-8278
Electronic ISSN 1600-0641
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 69
Issue 4
Pages 851-860
Keywords Hepatocyte; Inherited liver disease; Human-induced pluripotent stem cell; ?1-Antitrypsin deficiency; Inflammation
Public URL
Publisher URL
Additional Information This article is maintained by: Elsevier; Article Title: hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency; Journal Title: Journal of Hepatology; CrossRef DOI link to publisher maintained version:; Content Type: article; Copyright: © 2018 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.


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