Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells

Andrew A. Wilson, Lei Ying, Marc Liesa, Charis Patricia Segeritz, Jason A. Mills, Steven S. Shen, Jyhchang Jean, Geordie C. Lonza, Derek C. Liberti, Alex H. Lang, Jean Nazaire, Adam C. Gower, Franz Josef Müeller, Pankaj Mehta, Adriana Ordóñez, David A. Lomas, Ludovic Vallier, George J. Murphy, Gustavo Mostoslavsky, Avrum SpiraOrian S. Shirihai, Maria I. Ramirez, Paul Gadue, Darrell N. Kotton

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)873-885
Number of pages13
JournalStem Cell Reports
Volume4
Issue number5
DOIs
StatePublished - 12 May 2015
Externally publishedYes

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