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

Authors

Charis-Patricia Segeritz

Sheikh Tamir Rashid

Miguel Cardoso de Brito

Maria Paola Serra

Adriana Ordonez

Carola Maria Morell

Joseph E. Kaserman

Pedro Madrigal

NICK HANNAN NICK.HANNAN@NOTTINGHAM.AC.UK
Assistant Professor in Translational Stem Cell Biology

Laurent Gatto

Lu Tan

Andrew A. Wilson

Kathryn Lilley

Stefan J. Marciniak

Bibek Gooptu

David A. Lomas

Ludovic Vallier



Abstract

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.

Journal Article Type Article
Publication Date Oct 1, 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
APA6 Citation 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. https://doi.org/10.1016/j.jhep.2018.05.028
DOI https://doi.org/10.1016/j.jhep.2018.05.028
Keywords Hepatocyte; Inherited liver disease; Human-induced pluripotent stem cell; α1-Antitrypsin deficiency; Inflammation
Publisher URL https://www.sciencedirect.com/science/article/pii/S0168827818321135?via%3Dihub
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: https://doi.org/10.1016/j.jhep.2018.05.028; 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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