title: Cardiac applications for human pluripotent stem cells.
abstract: Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can self-renew indefinitely, while maintaining the capacity to differentiate into useful somatic cell types, including cardiomyocytes. As such, these stem cell types represent an essentially inexhaustible source of committed human cardiomyocytes of potential use in cell-based cardiac therapies, high-throughput screening and safety testing of new drugs, and modeling human heart development. These stem cell-derived cardiomyocytes have an unambiguous cardiac phenotype and proliferate robustly both in vitro and in vivo. Recent transplantation studies in preclinical models have provided exciting proof-of-principle for their use in infarct repair and in the formation of a "biological pacemaker". While these successes give reason for cautious optimism, major challenges remain to the successful application of hESCs (or hiPSCs) to cardiac repair, including the need for preparations of high cardiac purity, improved methods of delivery, and approaches to overcome immune rejection and other causes of graft cell death. In this review, we describe the phenotype of hESC- and hiPSC-derived cardiomyocytes, the state of preclinical transplantation studies with these cells, and potential approaches to overcome the aforementioned hurdles.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiba
authors.forename: Kip D
authors.initials: KD
authors.lastname: Hauch
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
mesh_terms: D002454:Cell Differentiation; D002469:Cell Separation; D053595:Embryonic Stem Cells / Q000166:cytology; D006331:Heart Diseases / Q000628:therapy*; D006801:Humans; D009203:Myocardial Infarction / Q000628:therapy; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000637:transplantation*; D023822:Tissue Engineering
references.citation: Circulation. 1998 Nov 24;98(21):2334-51
references.pmid: 9826323
references.citation: Nature. 2007 Jul 19;448(7151):313-7
references.pmid: 17554338
references.citation: Circulation. 2005 Jan 4;111(1):11-20
references.pmid: 15611367
references.citation: Differentiation. 1991 Feb;46(1):51-60
references.pmid: 1710586
references.citation: Nature. 2008 May 22;453(7194):524-8
references.pmid: 18432194
references.citation: Circulation. 2008 Jul 29;118(5):498-506
references.pmid: 18625891
references.citation: Nat Biotechnol. 2005 Jul;23(7):845-56
references.pmid: 16003373
references.citation: Circulation. 2002 Jan 1;105(1):93-8
references.pmid: 11772882
references.citation: J Exp Med. 2006 Oct 2;203(10):2315-27
references.pmid: 16954371
references.citation: Stem Cells. 2007 Sep;25(9):2200-5
references.pmid: 17540853
references.citation: Dev Dyn. 1994 Jun;200(2):155-62
references.pmid: 7919501
references.citation: Differentiation. 2008 Apr;76(4):357-70
references.pmid: 18021257
references.citation: Transplantation. 2005 Dec 15;80(11):1586-95
references.pmid: 16371930
references.citation: Nature. 2001 Apr 5;410(6829):701-5
references.pmid: 11287958
references.citation: Stem Cells. 2007 Feb;25(2):455-64
references.pmid: 17038665
references.citation: Dev Biol. 1998 Dec 15;204(2):407-19
references.pmid: 9882479
references.citation: Circ Res. 2003 Jul 11;93(1):32-9
references.pmid: 12791707
references.citation: Stem Cells. 2008 Aug;26(8):1961-72
references.pmid: 18483424
references.citation: Nature. 2008 Jan 10;451(7175):141-6
references.pmid: 18157115
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Dev Cell. 2006 Nov;11(5):723-32
references.pmid: 17084363
references.citation: Blood. 2005 Jun 15;105(12):4598-603
references.pmid: 15718421
references.citation: Stem Cells. 2005 Jun-Jul;23(6):772-80
references.pmid: 15917473
references.citation: Nat Biotechnol. 2001 Oct;19(10):971-4
references.pmid: 11581665
references.citation: Nature. 2007 Dec 6;450(7171):819-24
references.pmid: 18064002
references.citation: J Cardiovasc Pharmacol. 2003 Jul;42(1):113-7
references.pmid: 12827035
references.citation: Science. 1998 Nov 6;282(5391):1145-7
references.pmid: 9804556
references.citation: Circulation. 2002 Sep 3;106(10):1294-9
references.pmid: 12208808
references.citation: J Am Coll Cardiol. 2003 Apr 2;41(7):1078-83
references.pmid: 12679204
references.citation: FEBS Lett. 2000 Jul 28;478(1-2):151-8
references.pmid: 10922488
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19812-7
references.pmid: 17170140
references.citation: Nat Biotechnol. 2008 Jan;26(1):101-6
references.pmid: 18059259
references.citation: J Embryol Exp Morphol. 1985 Jun;87:27-45
references.pmid: 3897439
references.citation: J Thorac Cardiovasc Surg. 2003 Feb;125(2):361-9
references.pmid: 12579106
references.citation: Mol Pharmacol. 2004 Jul;66(1):33-44
references.pmid: 15213294
references.citation: Nature. 2007 Jul 19;448(7151):318-24
references.pmid: 17554336
references.citation: Nature. 1981 Jul 9;292(5819):154-6
references.pmid: 7242681
references.citation: Stem Cells. 2005 Apr;23(4):544-9
references.pmid: 15790775
references.citation: Ann Thorac Surg. 2002 Jun;73(6):1919-25; discussion 1926
references.pmid: 12078791
references.citation: Stem Cells. 2005 Oct;23(9):1221-7
references.pmid: 15955827
references.citation: Biochem Biophys Res Commun. 2006 Feb 10;340(2):573-82
references.pmid: 16376856
references.citation: Nat Med. 2006 Apr;12(4):452-8
references.pmid: 16582915
references.citation: Ann Thorac Surg. 1996 Sep;62(3):654-60; discussion 660-1
references.pmid: 8783989
references.citation: Stem Cells. 2004;22(6):972-80
references.pmid: 15536188
references.citation: J Appl Physiol (1985). 2002 Jan;92(1):288-96
references.pmid: 11744672
references.citation: Stem Cells. 2007 Dec;25(12):3038-44
references.pmid: 17872499
references.citation: FASEB J. 2007 Aug;21(10):2551-63
references.pmid: 17435178
references.citation: J Exp Zool. 1970 Nov;175(3):323-6
references.pmid: 5478937
references.citation: Biotechnol Bioeng. 2005 Sep 20;91(6):688-98
references.pmid: 15971228
references.citation: Nat Med. 2008 Feb;14(2):213-21
references.pmid: 18193059
references.citation: Am J Cardiol. 1989 Jan 1;63(1):1-6
references.pmid: 2462341
references.citation: Tissue Eng Part A. 2009 Jun;15(6):1211-22
references.pmid: 19063661
references.citation: Circ Res. 2002 Sep 20;91(6):501-8
references.pmid: 12242268
references.citation: J Struct Biol. 2007 Jun;158(3):307-17
references.pmid: 17257857
references.citation: Circulation. 1997 Nov 4;96(9 Suppl):II-188-93
references.pmid: 9386096
references.citation: Cell Biol Int. 2009 Mar;33(3):255-67
references.pmid: 19084605
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2883-8
references.pmid: 18287077
references.citation: Nat Biotechnol. 2008 Nov;26(11):1269-75
references.pmid: 18849973
references.citation: J Clin Invest. 1996 Dec 1;98(11):2512-23
references.pmid: 8958214
references.citation: Circulation. 2002 Apr 23;105(16):1943-8
references.pmid: 11997281
references.citation: N Engl J Med. 2004 Mar 4;350(10):1013-22
references.pmid: 14999113
references.citation: J Clin Invest. 1996 Jul 1;98(1):216-24
references.pmid: 8690796
references.citation: Nat Biotechnol. 2006 Feb;24(2):185-7
references.pmid: 16388305
references.citation: Circ Res. 2008 May 9;102(9):1008-10
references.pmid: 18436793
references.citation: Stem Cells. 2007 May;25(5):1136-44
references.pmid: 17255522
references.citation: Am J Pathol. 2005 Sep;167(3):663-71
references.pmid: 16127147
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9685-90
references.pmid: 17522258
references.citation: Lancet. 2005 Sep 17-23;366(9490):1005-12
references.pmid: 16168783
references.citation: Development. 1995 Dec;121(12):4203-14
references.pmid: 8575320
references.citation: Nat Med. 2004 Jan;10(1):55-63
references.pmid: 14702635
references.citation: Nat Med. 1998 Aug;4(8):929-33
references.pmid: 9701245
references.citation: Tissue Eng. 2003 Aug;9(4):767-78
references.pmid: 13678453
references.citation: J Pharmacol Exp Ther. 2005 Jan;312(1):316-23
references.pmid: 15340016
references.citation: Nature. 1997 Feb 27;385(6619):810-3
references.pmid: 9039911
references.citation: Trends Cardiovasc Med. 2007 Oct;17(7):240-6
references.pmid: 17936206
references.citation: J Clin Invest. 2001 Aug;108(3):407-14
references.pmid: 11489934
references.citation: Heart. 2007 Oct;93(10):1278-84
references.pmid: 17566061
references.citation: Nat Protoc. 2007;2(8):1963-72
references.pmid: 17703208
references.citation: J Mol Cell Cardiol. 2005 Dec;39(6):865-73
references.pmid: 16242146
references.citation: Circ Res. 2008 Nov 7;103(10):1058-71
references.pmid: 18988903
references.citation: Exp Mol Med. 2005 Oct 31;37(5):399-407
references.pmid: 16264264
references.citation: Blood. 2007 Dec 1;110(12):4111-9
references.pmid: 17761519
references.citation: Circulation. 2005 Aug 30;112(9 Suppl):I166-72
references.pmid: 16159810
references.citation: Circ Res. 2007 Aug 31;101(5):484-92
references.pmid: 17641227
references.citation: J Mol Cell Cardiol. 2008 Oct;45(4):462-74
references.pmid: 18775434
references.citation: Circulation. 2007 Sep 11;116(11 Suppl):I16-23
references.pmid: 17846298
references.citation: Nat Biotechnol. 2008 Jul;26(7):795-7
references.pmid: 18568017
references.citation: Eur J Cardiothorac Surg. 2006 Jan;29(1):50-5
references.pmid: 16337396
references.citation: Ann N Y Acad Sci. 2005 Jun;1047:50-65
references.pmid: 16093484
references.citation: J Physiol. 2004 Sep 1;559(Pt 2):479-96
references.pmid: 15243138
references.citation: Circulation. 1994 Jan;89(1):151-63
references.pmid: 8281642
references.citation: Circulation. 2005 Feb 1;111(4):442-50
references.pmid: 15687132
references.citation: Circulation. 2002 May 7;105(18):2136-8
references.pmid: 11994244
references.citation: Science. 2008 Nov 7;322(5903):945-9
references.pmid: 18818365
references.citation: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):e311-2
references.pmid: 18029907
references.citation: Circulation. 1996 Nov 1;94(9 Suppl):II337-40
references.pmid: 8901771
references.citation: Mol Ther. 2008 Jun;16(6):1129-37
references.pmid: 18431364
references.citation: Transplant Proc. 2004 Oct;36(8):2507-8
references.pmid: 15561297
references.citation: Circulation. 1996 Nov 1;94(9 Suppl):II332-6
references.pmid: 8901770
references.citation: Stem Cell Res. 2007 Oct;1(1):9-24
references.pmid: 19383383
references.citation: Dev Biol. 1995 Apr;168(2):567-74
references.pmid: 7729588
references.citation: Biochem Biophys Res Commun. 2006 Dec 15;351(2):321-7
references.pmid: 17069765
references.citation: Ann Thorac Surg. 2002 Nov;74(5):1568-75
references.pmid: 12440610
references.citation: Genes Dev. 1991 Sep;5(9):1513-23
references.pmid: 1653172
references.citation: Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2355-63
references.pmid: 14613910
references.citation: Nat Med. 2003 Sep;9(9):1195-201
references.pmid: 12910262
references.citation: Circulation. 2006 Sep 5;114(10):e385-484
references.pmid: 16935995
references.citation: Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634-8
references.pmid: 6950406
references.citation: Adv Drug Deliv Rev. 2008 Jan 14;60(2):277-85
references.pmid: 18006178
references.citation: J Thorac Cardiovasc Surg. 2000 Jun;119(6):1169-75
references.pmid: 10838534
references.citation: Circulation. 2008 Jul 29;118(5):507-17
references.pmid: 18625890
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Nat Mater. 2008 Dec;7(12):1003-10
references.pmid: 18978786
references.citation: Nature. 2007 Aug 30;448(7157):1015-21
references.pmid: 17625568
references.citation: Stem Cells Dev. 2006 Dec;15(6):931-41
references.pmid: 17253954
references.citation: Science. 2008 Nov 7;322(5903):949-53
references.pmid: 18845712
references.citation: Stem Cells Dev. 2009 Jan-Feb;18(1):161-72
references.pmid: 18510453
references.citation: J Intern Med. 2006 Jan;259(1):70-80
references.pmid: 16336515
references.citation: Ageing Res Rev. 2007 Dec;6(4):289-301
references.pmid: 17981518
references.citation: Circulation. 2003 Mar 4;107(8):1106-9
references.pmid: 12615786
references.citation: Biochem Biophys Res Commun. 2005 May 13;330(3):934-42
references.pmid: 15809086
references.citation: Nat Biotechnol. 2007 Sep;25(9):1015-24
references.pmid: 17721512
references.citation: Annu Rev Pathol. 2007;2:307-39
references.pmid: 18039102
references.citation: Cytotherapy. 2003;5(5):399-413
references.pmid: 14578102
references.citation: Circ Res. 2004 Apr 16;94(7):952-9
references.pmid: 14988226
references.citation: Circulation. 2003 Jun 3;107(21):2733-40
references.pmid: 12742992
references.citation: J Electrocardiol. 2004 Jan;37(1):19-24
references.pmid: 15132365
references.citation: Nat Biotechnol. 2004 Oct;22(10):1282-9
references.pmid: 15448703
references.citation: Circ Res. 2007 Feb 2;100(2):263-72
references.pmid: 17218605
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4391-6
references.pmid: 11917100
references.citation: Circ Res. 2005 Jul 8;97(1):8-15
references.pmid: 16002755
references.citation: J Mol Cell Cardiol. 2007 Oct;43(4):504-16
references.pmid: 17707399
references.citation: FASEB J. 2007 May;21(7):1345-57
references.pmid: 17284483
references.citation: J Am Coll Cardiol. 2007 Nov 6;50(19):1884-93
references.pmid: 17980256
references.citation: Circ Res. 2007 Aug 3;101(3):286-94
references.pmid: 17569886
references.citation: Mol Ther. 2007 Nov;15(11):2027-36
references.pmid: 17895862
references.citation: Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):446-50
references.pmid: 16023163
references.citation: Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H471-9
references.pmid: 15277190
references.citation: Trends Cardiovasc Med. 2007 May;17(4):134-40
references.pmid: 17482096
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Br Med Bull. 2008;87:31-47
references.pmid: 18790825
references.citation: Stem Cells. 2001;19(3):193-204
references.pmid: 11359944
references.citation: Exp Biol Med (Maywood). 2006 Dec;231(11):1753-62
references.pmid: 17138763
references.citation: Biotechnol Bioeng. 2009 Feb 1;102(2):493-507
references.pmid: 18767184