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

69 Scopus citations


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 (US)
Pages (from-to)873-885
Number of pages13
JournalStem Cell Reports
Issue number5
StatePublished - May 12 2015

Bibliographical note

Funding Information:
We are indebted to members of the Kotton, Wilson, and Ikonomou labs and CReM for helpful discussions. For essential technical support, we thank Amel Omari, Amulya Iyer, Peggy Russell, and Emily Porter. We are grateful to Dr. Yuriy Alekseyev of the Boston University Microarray Resource, Sherry Zang and Dr. Gang Liu for microarray processing, and Dr. Tomas Carroll for generous technical assistance. A.A.W. is supported by K08 HL103771, FAMRI 062572_YCSA, an Alpha-1 Foundation Research Grant, and a Boston University Department of Medicine Career Investment Award; P.G., L.Y., and P.M. are supported by NIH 1RC2HL101535-01; M.L. is an Evans Center Fellow and member of the Evans Center for Interdisciplinary Biomedical Research ARC on mitochondria; and D.N.K. is supported by NIH 1RC2HL101535-01, 1R01HL095993, 1R01HL108678, an Alpha-1 Foundation Award, and an ARC award from the Evans Center for Interdisciplinary Research at Boston University.

Publisher Copyright:
© 2015 The Authors.


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