Emergence of a Stage-Dependent Human Liver Disease Signature with Directed Differentiation of Alpha-1 Antitrypsin-Deficient iPS Cells

• Published in: Stem cell reports 2015-05, Vol.4 (5), p.873-885
• Main Authors: Wilson, Andrew A., Ying, Lei, Liesa, Marc, Segeritz, Charis-Patricia, Mills, Jason A., Shen, Steven S., Jean, Jyhchang, Lonza, Geordie C., Liberti, Derek C., Lang, Alex H., Nazaire, Jean, Gower, Adam C., Müeller, Franz-Josef, Mehta, Pankaj, Ordóñez, Adriana, Lomas, David A., Vallier, Ludovic, Murphy, George J., Mostoslavsky, Gustavo, Spira, Avrum, Shirihai, Orian S., Ramirez, Maria I., Gadue, Paul, Kotton, Darrell N.
• Format: Article
• Language: English
• Subjects: Alleles; alpha 1-Antitrypsin - analysis; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; Autophagy - drug effects; Carbamazepine - toxicity; Cell Differentiation; Cells, Cultured; DNA Methylation; Enzyme-Linked Immunosorbent Assay; Epigenomics; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Liver Diseases - metabolism; Liver Diseases - pathology; Mutation; Oligonucleotide Array Sequence Analysis; Transcriptome
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2015.02.021

Induced pluripotent stem cells (iPSCs) provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in vitro directed differentiation. Using iPSCs generated from a cohort carrying mutations (PiZZ) in the gene responsible for alpha-1 antitrypsin (AAT) deficiency, we find that the global transcriptomes of PiZZ iPSCs diverge from normal controls upon differentiation to hepatic cells. Expression of 135 genes distinguishes PiZZ iPSC-hepatic cells, providing potential clues to liver disease pathogenesis. The disease-specific cells display intracellular accumulation of mutant AAT protein, resulting in increased autophagic flux. Furthermore, we detect beneficial responses to the drug carbamazepine, which further augments autophagic flux, but adverse responses to known hepatotoxic drugs. Our findings support the utility of iPSCs as tools for drug development or prediction of toxicity. [Display omitted] •Patient iPSC-hepatic cells model disease features that normalize with gene editing•Disease-specific transcriptomic signature emerges only upon hepatic differentiation•Patient iPSC-hepatic cells are used to test response to drugs or toxicity in vitro In this report, Kotton and colleagues examine the global transcriptomic and epigenomic programs of iPSCs derived from diseased (AAT-deficient PiZZ) or normal human cohorts during directed differentiation. The PiZZ transcriptome diverges from controls upon reaching hepatic stage, when AAT is first expressed, providing potential clues to liver disease pathogenesis. PiZZ iPSC-hepatic cells model key liver disease features and demonstrate both therapeutic drug responsiveness and sensitivity to toxic agents.