SAHA increases chaperone expression and reduces Z-alpha-1-antitrypsin polymers in a patient specific iPSC-based liver model for alpha-1-antitrypsin deficiency

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Summary The most severe phenotype of alpha-1-antitrypsin deficiency (AATD) is caused by the Z-mutation within the SERPINA1 gene. The Glu342Lys substitution causes misfolding and polymerisation of the alpha-1-antitrypsin (AAT) protein, its accumulation in the ER and increases the susceptibility of hepatocytes towards ER-stress. Here, we present an induced pluripotent stem cell (iPSC)-based hepatic model to study AATD. We demonstrate that iPSCs from AATD patients differentiate equally well to hepatocyte-like cells (HLCs) as control iPSCs. We detected ZAAT polymers in patient-derived HLCs which could be reduced by SAHA or CBZ treatment. Transcriptome analyses revealed major differences in metabolism and signalling between control and AATD HLCs and indicated increased stress levels affecting intracellular organelles. Importantly, the transcriptomes of control and patient-derived cells separated into distinct clusters with respect to the expression of Heat-shock protein (HSP) encoding genes. SAHA treatment increased expression of various HSPs which might contribute towards reduced ZAAT polymers.

Authors 7

1. Nina Graffmann

   Düsseldorf University Hospital · Heinrich Heine University Düsseldorf

   Affiliation as printed

   Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany

2. Rabea Hokamp Aachen Department of Internal Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen · Düsseldorf University Hospital · Heinrich Heine University Düsseldorf

   Affiliation as printed

   Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany

   Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany

3. Christiane Loerch

   Düsseldorf University Hospital · Heinrich Heine University Düsseldorf

   Affiliation as printed

   Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany

4. Malin Fromme Aachen Department of Internal Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany

5. Wasco Wruck

   Düsseldorf University Hospital · Heinrich Heine University Düsseldorf

   Affiliation as printed

   Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany

6. Pavel Strnad Aachen Department of Internal Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen · Medizinische Universität Lausitz - Carl Thiem

   Affiliation as printed

   Department of Gastroenterology and Hepatology, Medical University Lausitz-Carl-Thiem, Cottbus, Germany

   Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany

7. James Adjaye corresponding

   King's College London · Düsseldorf University Hospital · Heinrich Heine University Düsseldorf

   Affiliation as printed

   Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany

   The School of Immunology & Microbial Sciences, Centre for Nephrology, Urology and Transplantation, King’s College London, Guy’s Campus, Great Maze Pond, London SE1 1UL, United Kingdom