title: The Use of Induced Pluripotent Stem Cells for the Study and Treatment of Liver Diseases.
abstract: Liver disease is a major global health concern. Liver cirrhosis is one of the leading causes of death in the world and currently the only therapeutic option for end-stage liver disease (e.g., acute liver failure, cirrhosis, chronic hepatitis, cholestatic diseases, metabolic diseases, and malignant neoplasms) is orthotropic liver transplantation. Transplantation of hepatocytes has been proposed and used as an alternative to whole organ transplant to stabilize and prolong the lives of patients in some clinical cases. Although these experimental therapies have demonstrated promising and beneficial results, their routine use remains a challenge due to the shortage of donor livers available for cell isolation, variable quality of those tissues, the potential need for lifelong immunosuppression in the transplant recipient, and high costs. Therefore, new therapeutic strategies and more reliable clinical treatments are urgently needed. Recent and continuous technological advances in the development of stem cells suggest they may be beneficial in this respect. In this review, we summarize the history of stem cell and induced pluripotent stem cell (iPSC) technology in the context of hepatic differentiation and discuss the potential applications the technology may offer for human liver disease modeling and treatment. This includes developing safer drugs and cell-based therapies to improve the outcomes of patients with currently incurable health illnesses. We also review promising advances in other disease areas to highlight how the stem cell technology could be applied to liver diseases in the future. © 2016 by John Wiley & Sons, Inc.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Hansel
authors.affiliation: Department of Biochemistry, University of Puerto Rico School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Davila
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Massoud
authors.initials: M
authors.lastname: Vosough
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Skvorak
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Department of Biomedical Sciences, Section of Experimental Pathology, Unit of Experimental Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marongiu
authors.affiliation: Genetically Modified Models Center of Emphasis, Pfizer, Groton, Connecticut.
authors.forename: William
authors.initials: W
authors.lastname: Blake
authors.affiliation: McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.|Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000637:transplantation; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D008107:Liver Diseases / Q000209:etiology / Q000628:therapy; D008115:Liver Regeneration; D044968:Regenerative Medicine / Q000379:methods*; D033581:Stem Cell Transplantation
keywords: cell therapy; cell transplantation; disease-specific induced pluripotent stem cells; human liver disease modeling; liver disease; metabolic liver disease; regenerative medicine
references.citation: Nature. 2009 Sep 17;461(7262):402-6
references.pmid: 19693009
references.citation: J Biol Chem. 2014 Feb 21;289(8):4555-61
references.pmid: 24362027
references.citation: Mol Biosyst. 2010 May;6(5):840-51
references.pmid: 20567770
references.citation: J Biol Chem. 2011 Sep 23;286(38):33520-32
references.pmid: 21799003
references.citation: Stem Cell Rev. 2010 Jun;6(2):297-306
references.pmid: 20180049
references.citation: Nat Biotechnol. 2005 Dec;23(12):1534-41
references.pmid: 16258519
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16825-30
references.pmid: 21949375
references.citation: Science. 2008 Nov 7;322(5903):945-9
references.pmid: 18818365
references.citation: Nature. 2008 Jan 10;451(7175):141-6
references.pmid: 18157115
references.citation: Stem Cell Rev. 2010 Dec;6(4):622-32
references.pmid: 20821352
references.citation: Cell Transplant. 2014 Jan;23(1):27-38
references.pmid: 23394081
references.citation: Genetics. 2010 Oct;186(2):451-9
references.pmid: 20628038
references.citation: BMC Dev Biol. 2010;10:81
references.pmid: 20682060
references.citation: Cell Stem Cell. 2009 Sep 4;5(3):237-41
references.pmid: 19716359
references.citation: Cell Res. 2008 May;18(5):600-3
references.pmid: 18414447
references.citation: Nat Biotechnol. 2010 May;28(5):521-6
references.pmid: 20436460
references.citation: Genes Cells. 2009 Dec;14(12):1395-404
references.pmid: 19912344
references.citation: Circ Res. 2014 Aug 15;115(5):488-92
references.pmid: 24916110
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18283-8
references.pmid: 21990348
references.citation: Nature. 1997 Feb 27;385(6619):810-3
references.pmid: 9039911
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14234-9
references.pmid: 21821793
references.citation: EMBO Mol Med. 2012 May;4(5):380-95
references.pmid: 22407749
references.citation: Cell Stem Cell. 2012 May 4;10(5):570-82
references.pmid: 22542160
references.citation: Cell Stem Cell. 2010 Oct 8;7(4):451-4
references.pmid: 20887951
references.citation: Stem Cells. 2015 Apr;33(4):1055-62
references.pmid: 25524146
references.citation: Cell J. 2014 Feb 3;16(1):63-72
references.pmid: 24518969
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19467-72
references.pmid: 20974949
references.citation: Cell Res. 2009 Nov;19(11):1233-42
references.pmid: 19736565
references.citation: Nature. 2009 Jul 2;460(7251):53-9
references.pmid: 19483674
references.citation: Gastroenterology. 2012 Apr;142(4):907-17
references.pmid: 22245845
references.citation: Hepatology. 2010 Jan;51(1):297-305
references.pmid: 19998274
references.citation: Nature. 2009 Jan 15;457(7227):277-80
references.pmid: 19098894
references.citation: Hepatology. 2010 May;51(5):1810-9
references.pmid: 20432258
references.citation: Clin Pharmacol Ther. 2011 May;89(5):655-61
references.pmid: 21430656
references.citation: Stem Cells. 2008 Aug;26(8):1998-2005
references.pmid: 18511599
references.citation: Nat Methods. 2009 Nov;6(11):805-8
references.pmid: 19838168
references.citation: Nat Med. 2011 Dec;17(12):1657-62
references.pmid: 22120178
references.citation: FEBS Lett. 2014 Nov 3;588(21):3954-8
references.pmid: 25241167
references.citation: Science. 1998 Nov 6;282(5391):1145-7
references.pmid: 9804556
references.citation: Curr Gene Ther. 2013 Apr;13(2):120-32
references.pmid: 23444872
references.citation: Stem Cells. 2012 May;30(5):997-1007
references.pmid: 22378611
references.citation: Int J Exp Pathol. 2008 Dec;89(6):401-9
references.pmid: 19134049
references.citation: Nat Biotechnol. 2009 Nov;27(11):1033-7
references.pmid: 19826408
references.citation: Stem Cell Res. 2013 Jul;11(1):563-73
references.pmid: 23644508
references.citation: Differentiation. 2010 Sep-Oct;80(2-3):123-9
references.pmid: 20510497
references.citation: Stem Cells Transl Med. 2013 Sep;2(9):641-54
references.pmid: 23926210
references.citation: Stem Cells. 2012 Apr;30(4):631-42
references.pmid: 22893457
references.citation: Cell Stem Cell. 2011 Apr 8;8(4):357-9
references.pmid: 21474098
references.citation: Cell Stem Cell. 2013 Jun 6;12(6):656-68
references.pmid: 23746975
references.citation: Gastroenterology. 2009 Mar;136(3):990-9
references.pmid: 19026649
references.citation: Cell Stem Cell. 2011 Dec 2;9(6):588-98
references.pmid: 22136932
references.citation: Stem Cells Int. 2011;2011:498132
references.pmid: 21904557
references.citation: Cell Stem Cell. 2013 Apr 4;12(4):407-12
references.pmid: 23352605
references.citation: Stem Cells. 2009 Mar;27(3):559-67
references.pmid: 19259936
references.citation: Stem Cells. 2011 Nov;29(11):1717-26
references.pmid: 21898685
references.citation: Cell Stem Cell. 2008 Oct 9;3(4):402-15
references.pmid: 18940732
references.citation: J Biol Chem. 2014 Feb 21;289(8):4578-84
references.pmid: 24362040
references.citation: Cell Stem Cell. 2010 Nov 5;7(5):618-30
references.pmid: 20888316
references.citation: Development. 2013 Aug;140(15):3285-96
references.pmid: 23861064
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2544-8
references.pmid: 22308485
references.citation: Nat Biotechnol. 2014 Jun;32(6):551-3
references.pmid: 24681508
references.citation: J Biol Chem. 2008 Nov 14;283(46):31601-7
references.pmid: 18782754
references.citation: Nat Biotechnol. 2011 Sep;29(9):829-34
references.pmid: 21841799
references.citation: Science. 2012 Nov 30;338(6111):1155-6
references.pmid: 23197518
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Methods Mol Biol. 2010;640:491-509
references.pmid: 20645070
references.citation: Nat Methods. 2010 Mar;7(3):197-9
references.pmid: 20139967
references.citation: Liver Int. 2012 May;32(5):732-41
references.pmid: 22292891
references.citation: J Vis Exp. 2011;(56):e2969
references.pmid: 22064456
references.citation: Hepatology. 2012 Apr;55(4):1193-203
references.pmid: 22095466
references.citation: Cell. 2009 Mar 6;136(5):964-77
references.pmid: 19269371
references.citation: Nat Biotechnol. 2007 Aug;25(8):903-10
references.pmid: 17664939
references.citation: Stem Cells Transl Med. 2013 Jul;2(7):505-9
references.pmid: 23757504
references.citation: EMBO J. 2014 Mar 3;33(5):409-17
references.pmid: 24500035
references.citation: Stem Cells Transl Med. 2014 Dec;3(12):1429-34
references.pmid: 25298370
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7886-91
references.pmid: 20385825
references.citation: Front Cell Dev Biol. 2014 Feb 13;2:2
references.pmid: 25364711
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Stem Cell Rev. 2013 Aug;9(4):493-504
references.pmid: 22076752
references.citation: Hepatology. 2007 May;45(5):1229-39
references.pmid: 17464996
references.citation: Science. 2011 Oct 28;334(6055):474
references.pmid: 21979934
references.citation: Development. 2011 Oct;138(19):4143-53
references.pmid: 21852396
references.citation: Arthritis Res Ther. 2014;16(1):R41
references.pmid: 24490617
references.citation: Curr Protoc Stem Cell Biol. 2014;30:1G.5.1-12
references.pmid: 25081564
references.citation: Biochem Biophys Res Commun. 2009 Sep 25;387(3):482-8
references.pmid: 19615974
references.citation: Hum Mol Genet. 2011 Aug 15;20(16):3176-87
references.pmid: 21593220
references.citation: Sci Transl Med. 2011 May 11;3(82):82ra39
references.pmid: 21562231
references.citation: Nature. 2014 Oct 16;514(7522):380-4
references.pmid: 25119044
references.citation: Nature. 2010 Feb 25;463(7284):1042-7
references.pmid: 20027182
references.citation: Cell Reprogram. 2010 Jun;12(3):237-47
references.pmid: 20698766
references.citation: Hepatology. 2013 Jun;57(6):2458-68
references.pmid: 23325555
references.citation: Mol Ther. 2010 Feb;18(2):386-93
references.pmid: 19997091
references.citation: Mol Cell Neurosci. 2010 Nov;45(3):258-66
references.pmid: 20603216
references.citation: PLoS One. 2010;5(7):e11756
references.pmid: 20668695
references.citation: Cell Stem Cell. 2013 Oct 3;13(4):382-4
references.pmid: 24094319
references.citation: Stem Cell Res Ther. 2012;3(5):38
references.pmid: 23021082
references.citation: Biol Pharm Bull. 2013;36(2):182-8
references.pmid: 23370349
references.citation: Nature. 2010 May 13;465(7295):175-81
references.pmid: 20418860
references.citation: Histochem Cell Biol. 2014 Aug;142(2):217-26
references.pmid: 24477550
references.citation: Nat Cell Biol. 2011 Nov;13(11):1353-60
references.pmid: 22020437
references.citation: Nature. 2011 Oct 20;478(7369):391-4
references.pmid: 21993621
references.citation: Nat Protoc. 2014 Mar;9(3):729-40
references.pmid: 24577362
references.citation: Curr Top Med Chem. 2011;11(13):1621-37
references.pmid: 21446908
references.citation: Cell Stem Cell. 2008 Nov 6;3(5):475-9
references.pmid: 18983962
references.citation: Biomaterials. 2010 Dec;31(35):9221-31
references.pmid: 20832855
references.citation: J Hepatol. 2012 Sep;57(3):628-36
references.pmid: 22659344
references.citation: Nat Cell Biol. 2009 Feb;11(2):197-203
references.pmid: 19136965
references.citation: Science. 2008 Aug 1;321(5889):699-702
references.pmid: 18276851
references.citation: PLoS One. 2014;9(1):e86372
references.pmid: 24466060
references.citation: Circ Res. 2009 Feb 27;104(4):e30-41
references.pmid: 19213953
references.citation: J Biol Chem. 2014 Feb 21;289(8):4594-9
references.pmid: 24362028
references.citation: J Biol Chem. 2010 Apr 9;285(15):11227-34
references.pmid: 20139068
references.citation: Stem Cells. 2010 Apr;28(4):674-86
references.pmid: 20135682
references.citation: Stem Cells. 2008 Apr;26(4):894-902
references.pmid: 18238852
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12538-43
references.pmid: 22802639
references.citation: Science. 2008 Aug 29;321(5893):1218-21
references.pmid: 18669821
references.citation: J Biol Chem. 2011 Apr 8;286(14):12417-28
references.pmid: 21285354
references.citation: Stem Cells Transl Med. 2012 May;1(5):409-21
references.pmid: 23197820
references.citation: Nat Biotechnol. 2008 Nov;26(11):1269-75
references.pmid: 18849973
references.citation: Toxicol Sci. 2014 Jul;140(1):236-45
references.pmid: 24752503
references.citation: Science. 2009 May 8;324(5928):797-801
references.pmid: 19325077
references.citation: Nat Biotechnol. 2008 Nov;26(11):1276-84
references.pmid: 18931654
references.citation: Biochem Biophys Res Commun. 2010 Mar 26;394(1):189-93
references.pmid: 20188704
references.citation: J Clin Invest. 2010 Sep;120(9):3127-36
references.pmid: 20739751
references.citation: Cell Stem Cell. 2008 Sep 11;3(3):346-53
references.pmid: 18786421
references.citation: Nat Chem Biol. 2013 Aug;9(8):514-20
references.pmid: 23728495
references.citation: Stem Cell Res. 2010 Jul;5(1):4-22
references.pmid: 20483202
references.citation: Stem Cells. 2008 May;26(5):1117-27
references.pmid: 18292207
references.citation: Cell Stem Cell. 2009 Apr 3;4(4):348-58
references.pmid: 19341624
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):472-6
references.pmid: 19481515
references.citation: Tissue Eng Part C Methods. 2009 Jun;15(2):297-306
references.pmid: 19196121
references.citation: J Hepatol. 2011 Jan;54(1):98-107
references.pmid: 20933294
references.citation: Cell Stem Cell. 2013 Jun 6;12(6):669-77
references.pmid: 23746976
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Biochem Biophys Res Commun. 2009 Aug 7;385(4):497-502
references.pmid: 19464263
references.citation: Hepatology. 2010 May;51(5):1754-65
references.pmid: 20301097
references.citation: Nat Biotechnol. 2014 Aug;32(8):724-6
references.pmid: 25093882
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12301-6
references.pmid: 18719101
references.citation: Nature. 2010 Sep 16;467(7313):285-90
references.pmid: 20644535
references.citation: Cell Transplant. 2012;21(5):815-25
references.pmid: 21944493
references.citation: Stem Cells Dev. 2013 Oct 15;22(20):2693-705
references.pmid: 23731381
references.citation: Cell Stem Cell. 2008 Aug 7;3(2):182-95
references.pmid: 18682240
references.citation: Nature. 2011 Jun 9;474(7350):212-5
references.pmid: 21572395
references.citation: Nat Protoc. 2013 Nov;8(11):2281-308
references.pmid: 24157548
references.citation: Stem Cells. 2007 Jan;25(1):29-38
references.pmid: 17204604
references.citation: Nat Commun. 2014;5:3903
references.pmid: 24875164
references.citation: Regen Med. 2010 Jul;5(4):557-68
references.pmid: 20632859
references.citation: Nat Biotechnol. 2010 Aug;28(8):848-55
references.pmid: 20644536
references.citation: J Clin Invest. 2010 Jan;120(1):51-9
references.pmid: 20051636
references.citation: Mol Ther. 2015 Mar;23(3):570-7
references.pmid: 25418680
references.citation: Stem Cells Transl Med. 2014 Nov;3(11):1253-8
references.pmid: 25359995
references.citation: Cell. 2008 Sep 5;134(5):877-86
references.pmid: 18691744
references.citation: J Cell Sci. 2011 Jun 15;124(Pt 12):1992-2000
references.pmid: 21610099