title: Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells.
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.
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ying
authors.affiliation: Evans Center for Interdisciplinary Research, Department of Medicine, Mitochondria ARC, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine and Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Charis-Patricia
authors.initials: CP
authors.lastname: Segeritz
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Mills
authors.affiliation: Division of Computational Biomedicine and Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Shen
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Jyhchang
authors.initials: J
authors.lastname: Jean
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Geordie C
authors.initials: GC
authors.lastname: Lonza
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Liberti
authors.affiliation: Physics Department, Boston University, Boston, MA 02215, USA.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Lang
authors.affiliation: The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Nazaire
authors.affiliation: Division of Computational Biomedicine and Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Gower
authors.affiliation: Zentrum für Integrative Psychiatrie, Universitätsklinikums Schleswig-Holstein, Kiel 24105, Germany.
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Müeller
authors.affiliation: Physics Department, Boston University, Boston, MA 02215, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Mehta
authors.affiliation: Cambridge Institute for Medical Research, Cambridge CB0 2XY, UK.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ordóñez
authors.affiliation: Cambridge Institute for Medical Research, Cambridge CB0 2XY, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine and Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Murphy
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mostoslavsky
authors.affiliation: Division of Computational Biomedicine and Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.affiliation: Evans Center for Interdisciplinary Research, Department of Medicine, Mitochondria ARC, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.affiliation: The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Ramirez
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gadue
authors.affiliation: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA. Electronic address: dkotton@bu.edu.
authors.forename: Darrell N
authors.initials: DN
authors.lastname: Kotton
mesh_terms: D000483:Alleles; D001343:Autophagy / Q000187:drug effects; D002220:Carbamazepine / Q000633:toxicity; D002454:Cell Differentiation; D002478:Cells, Cultured; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D057890:Epigenomics; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000515:alpha 1-Antitrypsin; D002220:Carbamazepine
references.citation: Hepatology. 2013 May;57(5):2049-60
references.pmid: 23197448
references.citation: Hepatology. 2013 Jun;57(6):2458-68
references.pmid: 23325555
references.citation: Development. 2013 Aug;140(15):3285-96
references.pmid: 23861064
references.citation: Blood. 2013 Jul 18;122(3):376-85
references.pmid: 23723449
references.citation: Nat Chem Biol. 2013 Aug;9(8):514-20
references.pmid: 23728495
references.citation: Blood. 2013 Sep 19;122(12):2047-51
references.pmid: 23940280
references.citation: Stem Cell Reports. 2013;1(5):451-63
references.pmid: 24286032
references.citation: Am J Respir Crit Care Med. 2014 Jan 15;189(2):183-93
references.pmid: 24279752
references.citation: Stem Cells Transl Med. 2014 Feb;3(2):141-8
references.pmid: 24375539
references.citation: Arch Toxicol. 2014 Jul;88(7):1427-37
references.pmid: 24912781
references.citation: J Hepatol. 2015 Mar;62(3):581-9
references.pmid: 25457200
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Nov;279(5):G961-74
references.pmid: 11052993
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Nov;283(5):G1156-65
references.pmid: 12381530
references.citation: Chest. 2002 Nov;122(5):1818-29
references.pmid: 12426287
references.citation: Biol Pharm Bull. 2003 Jul;26(7):931-5
references.pmid: 12843613
references.citation: J Immunol. 2004 May 1;172(9):5722-6
references.pmid: 15100318
references.citation: J Cell Biol. 2004 May 10;165(3):347-56
references.pmid: 15123740
references.citation: N Engl J Med. 1986 Mar 20;314(12):736-9
references.pmid: 3485248
references.citation: Am J Med. 1988 Jun 24;84(6A):13-31
references.pmid: 3289385
references.citation: Am J Physiol. 1989 Oct;257(4 Pt 1):L147-62
references.pmid: 2679136
references.citation: J Clin Invest. 1990 May;85(5):1343-52
references.pmid: 2185272
references.citation: J Biol Chem. 1990 Nov 25;265(33):20463-8
references.pmid: 2122976
references.citation: Nature. 1992 Jun 18;357(6379):605-7
references.pmid: 1608473
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9014-8
references.pmid: 8090762
references.citation: EMBO J. 1995 Jun 1;14(11):2580-8
references.pmid: 7781611
references.citation: J Biol Chem. 2005 Nov 25;280(47):39002-15
references.pmid: 16183649
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Hepatology. 2007 May;45(5):1313-23
references.pmid: 17464974
references.citation: EMBO J. 2008 Jan 23;27(2):433-46
references.pmid: 18200046
references.citation: Am J Respir Cell Mol Biol. 2008 Aug;39(2):133-41
references.pmid: 18323534
references.citation: Cell. 2008 Sep 5;134(5):877-86
references.pmid: 18691744
references.citation: Nature. 2009 Jan 15;457(7227):277-80
references.pmid: 19098894
references.citation: Hepatology. 2009 Jul;50(1):275-81
references.pmid: 19444872
references.citation: Hepatology. 2010 Jan;51(1):297-305
references.pmid: 19998274
references.citation: J Clin Invest. 2010 Jan;120(1):379-89
references.pmid: 20038801
references.citation: J Immunol. 2010 Apr 15;184(8):4538-46
references.pmid: 20228200
references.citation: Science. 2010 Jul 9;329(5988):229-32
references.pmid: 20522742
references.citation: J Clin Invest. 2010 Sep;120(9):3127-36
references.pmid: 20739751
references.citation: Stem Cells. 2010 Oct;28(10):1728-40
references.pmid: 20715179
references.citation: Nat Methods. 2011 Apr;8(4):315-7
references.pmid: 21378979
references.citation: J Clin Invest. 2011 Jun;121(6):2313-25
references.pmid: 21537085
references.citation: Nature. 2011 Oct 20;478(7369):391-4
references.pmid: 21993621
references.citation: Cell Stem Cell. 2012 Apr 6;10(4):371-84
references.pmid: 22482503
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12538-43
references.pmid: 22802639
references.citation: J Gen Physiol. 2013 Jan;141(1):61-72
references.pmid: 23277474