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

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posted on 09.08.2019, 13:14 by C-P Segeritz, ST Rashid, MC de Brito, MP Serra, A Ordonez, CM Morell, JE Kaserman, P Madrigal, NRF Hannan, L Gatto, L Tan, AA Wilson, K Lilley, SJ Marciniak, B Gooptu, DA Lomas, L Vallier
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.


CPS is funded through a Children’s Liver Disease Foundation (CLDF) studentship. DAL is funded by the Medical Research Council, Wellcome Trust, GlaxoSmithKline, the Rosetrees Trust, EPSRC and UCLH NIHR Biomedical Research Centre. LV, PM, MCB, NH are funded by ERC Relieve-IMDs and ERC advanced grant New-Chol, Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre, and the core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. STR is funded by an MRC Clinician Scientist Fellowship award.



Journal of Hepatology, 2018, 69 (4), pp. 851-860

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/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation


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Journal of Hepatology


Elsevier for European Association for the Study of the Liver (EASL)



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Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.jhep.2018.05.028