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
Sheikh Tamir Rashid
Miguel Cardoso de Brito
Maria Paola Serra
Carola Maria Morell
Joseph E. Kaserman
NICK HANNAN NICK.HANNAN@NOTTINGHAM.AC.UK
Assistant Professor in Translational Stem Cell Biology
Andrew A. Wilson
Stefan J. Marciniak
David A. Lomas
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.
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.
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.
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|
|Peer Reviewed||Peer Reviewed|
|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|
|Keywords||Hepatocyte; Inherited liver disease; Human-induced pluripotent stem cell; α1-Antitrypsin deficiency; Inflammation|
|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.|
hiPSC hepatocyte model
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