Induced pluripotent stem cells (iPS cells or iPSCs) are typically derived by transfection of certain stem cell-associated genes into non-pluripotent cells, such as adult fibroblasts (typically adult somatic cells). Various diseases can be modeled through iPSC technology. The important implication of iPSCs to offer an unprecedented opportunity to recapitulate pathologic human tissue formation in vitro has generated great excitement and interest in the whole biomedical research community. Long QT syndrome (LQTS), an inherited heart disease, is characterized by prolonged QT interval on a surface electrocardiogram. LQTS presents with life-threatening cardiac arrhythmias, which can lead to fainting, syncope, and sudden death. The iPSC-derived cardiomyocytes from LQTS patients offer a potentially unlimited source of materials for biomedical study. They can be used to recapitulate complex physiological phenotypes, probe toxicological testing and drug screening, clarify the novel mechanistic insights and may also rectify gene defects at the cellular and molecular level. Despite the emerging challenges, iPSC technology has been increasingly recognized as a valuable and growing toolkit for modeling LQTS over other various models of human diseases.
LehtonenAFodstadHLaitinen-ForsblomPToivonenLKontulaKSwanH. Further evidence of inherited long QT syndrome gene mutations in antiarrhythmic drug-associated torsades de pointes. Heart Rhythm2007; 4: 603–7.
7.
BokilNJBaisdenJMRadfordDJSummersKM. Molecular genetics of long QT syndrome. Mol Gene Metabol2010; 101: 1–8.
8.
TiscorniaGVivasELBelmonteJCI. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med2011; 17: 1570–6.
9.
DongerCDenjoyIBerthetMNeyroudNCruaudCBennaceurMChivoretGSchwartzKCoumelPGuicheneyP. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation1997; 96: 2778–81.
10.
ChouabeCNeyroudNRichardPDenjoyIHainqueBRomeyGDriciMDGuicheneyPBarhaninJ. Novel mutations in KvLQT1 that affect I-ks activation through interactions with Isk. Cardiovasc Res2000; 45: 971–80.
11.
WangZTristani-FirouziMXuQLinMKeatingMTSanguinettiMC. Functional effects of mutations in KvLQT1 that cause long QT syndrome. J Cardiovas Electrophysiol1999; 10: 817–26.
MalanDFriedrichsSFleischmannBKSasseP. Cardiomyocytes obtained from induced pluripotent stem cells with long-QT syndrome 3 recapitulate typical disease‐specific features in vitro. Circ Res2011; 109: 841–U48.
14.
NuyensDStenglMDugarmaaSRossenbackerTCompernolleVRudyYSmitsJFFlamengWClancyCEMoonsLVosMADewerchinMBenndorfKCollenDCarmelietECarmelietP. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med2001; 7: 1021–7.
15.
RosenzweigA. Illuminating the potential of pluripotent stem cells. New Engl J Med2010; 363: 1471–2.
16.
PoutonCWHaynesJM. Embryonic stem cells as a source of models for drug discovery. Nat Rev Drug Discov2007; 6: 605–16.
17.
TakahashiKYamanakaS. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell2006; 126: 663–76.
18.
ZhangRZhangLHXieX. iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery. Acta Pharmacol Sin2013; 34: 765–76.
19.
HockemeyerDSoldnerFBeardCGaoQMitalipovaMDeKelverRCKatibahGEAmoraRBoydstonEAZeitlerBMengXDMillerJCZhangLRebarEJGregoryPD. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol2009; 27: 851–U110.
20.
ZouJMaederMLMaliPPruett-MillerSMThibodeau-BegannySChouB-KChenGBYeZHParkIHDaleyGQPorteusMHJoungJKChengL. Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell2009; 5: 97–110.
21.
SalewskiRPFEftekharpourEFehlingsMG. Are induced pluripotent stem cells the future of cell-based regenerative therapies for spinal cord injury?J Cell Physiol2010; 222: 515–21..
22.
HouPLiYZhangXLiuCGuanJYLiHGZhaoTYeJQYangWFLiuKGeJXuJZhangQZhaoYDengHK. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science2013; 341: 651–4.
23.
SahaKJaenischR. Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell2009; 5: 584–95.
24.
ItzhakiIMaizelsLHuberIZwi-DantsisLCaspiOWintersternAFeldmanOGepsteinAArbelGHammermanHBoulosMGepsteinL. Modelling the long QT syndrome with induced pluripotent stem cells. Nature2011; 471: 225–U113.
MullerLUWSchlaegerTMDeVineALWilliamsDA. Induced pluripotent stem cells as a tool for gaining new insights into Fanconi anemia. Cell Cycle2012; 11: 2985–90.
27.
Corti S, Nizzardo M, Simone C, Falcone M, Nardini M, Ronchi D, Donadoni C, Salani S, Riboldi G, Magri F, Menozzi G, Bonaglia C, Rizzo F, Bresolin N, Comi GP. Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy. Sci Transl Med 2012;4(165):165ra162.
28.
LeeGPapapetrouEPKimHChambersSMTomishimaMJFasanoCAGanatYMMenonJShimizuFVialeATabarVSadelainMStuderL. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature2009; 461: 402–U100.
29.
XieCQHuangHWeiSSongLSZhangJRitchieRPChenLBZhangMChenYE. A comparison of murine smooth muscle cells generated from embryonic versus induced pluripotent stem cells. Stem Cells Dev2009; 18: 741–8.
30.
MauritzCSchwankeKReppelMNeefSKatsirntakiKMaierLSNguemoFMenkeSHausteinMHeschelerJHasenfussGMartinU. Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation2008; 118: 507–17.
31.
NarazakiGUosakiHTeranishiMOkitaKKimBMatsuokaSYamanakaSYamashitaJK. Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation2008; 118: 498–506.
32.
TakahashiKTanabeKOhnukiMNaritaMIchisakaTTomodaKYamanakaS. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell2007; 131: 861–72.
33.
ZhangJWilsonGFSoerensAGKoonceCHYuJPalecekSPThomsonJAKampTJ. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res2009; 104: e30–41.
34.
IedaMFuJ-DDelgado-OlguinPVedanthamVHayashiYBruneauBGSrivastavaD. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell2010; 142: 375–86.
35.
EfeJAHilcoveSKimJZhouHOuyangKWangGChenJDingS. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol2011; 13: 215–U61.
36.
HaaseAOlmerRSchwankeKWunderlichSMerkertSHessCDingS. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell2009; 5: 434–41.
37.
NovakAShtrichmanRGermanguzISegevHZeevi-LevinNFishmanBMandelYEBaradLDomevHKottonDMostoslavskyGBinahOItskovitz-EldorJ. Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. Cell Reprogram2010; 12: 665–78.
38.
Zwi-Dantsis L, Huber I, Habib M, Winterstern A, Gepstein A, Arbel G, Gepstein L. Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients. Eur Heart J 2012;34:1575–86.
39.
MorettiABellinMWellingAJungCBLamJTBott-FluegelLDornTGoedelAHohnkeCHofmannFSeyfarthMSinneckerDSchomigALaugwitzKL. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. New Engl J Med2010; 363: 1397–409.
40.
MatsaERajamohanDDickEYoungLMellorIStaniforthAStaniforthADenningC. Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J2011; 32: 952–62.
41.
GermanguzISedanOZeevi-LevinNShtrichmanRBarakEZiskindAEliyahuSMeiryGAmitMItskovitz-EldorJBinahO. Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J Cell Mol Med2011; 15: 38–51.
42.
MehtaASequieraGLSudibyoYJunLWongPLiewRShimW. Derivation and characterization of transgene free induced pluripotent stem cell derived cardiomyocytes from Asian patient with long QT syndrome. Eur Heart J2012; 33: 22–22.
43.
LahtiALKujalaVJChapmanHKoivistoA-PPekkanen-MattilaMKerkelaEHyttinenJKontulaKSwanHConklinBRYamanakaSSilvennoinenOAalto-SetalaK. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Models Mechan2012; 5: 220–30.
44.
KampTJ. An electrifying iPSC disease model: long QT syndrome Type 2 and heart cells in a dish. Cell Stem Cell2011; 8: 130–1.
45.
OkataSYuasaSYamaneTFurukawaTFukudaK. The generation of induced pluripotent stem cells from a patient with KCNH2 G603D, without LQT2 disease associated symptom. J Med Dental Sci2013; 60: 17–22.
46.
Sadguna YB, Jianhua Z, Amanda H, Sarah P, Joyce MT, Tisha N, Wen BW, Bradley JS, Kathleen RM, Lee LE, Kate MO, Carmen RV, Jonathan CM, Michael JA, James AT, Timothy JK, Craig TJ. Loss of IKr in LQT2 Patient iPS-derived Cardiomyocytes: Nonsense Mediated Decay as a Potential Mechanism? See circ.ahajournals.org/cgi/content/meeting_abstract/A15643 (accessed 26 May 2011).
47.
YazawaMHsuehBJiaXPascaAMBernsteinJAHallmayerJDolmetschRE. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature2011; 471: 230–U120.
Matsa E, Dixon JE, Medway C, Georgiou O, Patel MJ, Morgan K, Kemp PJ, Staniforth A, Mellor I, Denning C. Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocyte. Eur Heart J 2013 Mar 6 [Epub ahead of print].
50.
PrioriSGNapolitanoCCantuFBrownAMSchwartzPJ. Differential response to Na+ channel blockade, beta-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-QT syndrome. Circ Res1996; 78: 1009–15.
51.
KeatingMAtkinsonDDunnCTimothyKVincentGMLeppertM. Linkage of a cardiac-arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science1991; 252: 704–6.
52.
CurranMESplawskiITimothyKWVincentGMGreenEDKeatingMT. A molecular-basis for cardiac-arrhythmia – hERG mutations cause long QT syndrome. Cell1995; 80: 795–803.
53.
HedleyPLJorgensenPSchlamowitzSWangariRMoolman-SmookJBrinkPABrinkPAKantersJKCorfieldVAChristiansenM. The genetic basis of long QT and short QT syndromes: a mutation update. Hum Mutat2009; 30: 1486–511.
54.
Yang Y, Yang Y, Liang B, Liu J, Li J, Grunnet M, Grunnet M, Olesen SP, Rasmussen HB, Ellinor PT, Gao LJ, Lin XP, Li L, Wang L, Xiao JJ, Liu Y, Liu Y, Zhang SL, Liang DD, Peng LY, Jespersen T, Chen YH. Am J Hum Gene 2010;86:872–80.
55.
DelisleBPAnsonBDRajamaniSJanuaryCT. Biology of cardiac arrhythmias – ion channel protein trafficking. Circ Res2004; 94: 1418–28.
56.
GongQZhangLVincentGMHorneBDZhouZ. Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome. Circulation2007; 116: 17–24.
57.
DaviesBMorrisT. Physiological-parameters in laboratory-animals and humans. Pharma Res1993; 10: 1093–5.
58.
SothernRBGruberSA. Further commentary – physiological-parameters in laboratory-animals and humans. Pharma Res1994; 11: 349–50.
59.
MilanDJMacRaeCA. Animal models for arrhythmias. Cardiovas Res2005; 67: 426–37.
60.
DicksonMGagnonJP. The cost of new drug discovery and development. Discovery Med2004; 4: 172–9.
61.
DiMasiJAHansenRWGrabowskiHG. The price of innovation: new estimates of drug development costs. J Health Econom2003; 22: 151–85.
62.
LoRussoPM. Phase 0 clinical trials: an answer to drug development stagnation?J Clin Oncol2009; 27: 2586–8..
63.
BarterPJCaulfieldMErikssonMGrundySMKasteleinJJPKomajdaMLopez-SendonJMoscaLTardifJWatersDDShearCLRevkinJHBuhrKAFisherMRTallARBrewerB. Effects of torcetrapib in patients at high risk for coronary events. New Engl J Med2007; 357: 2109–22.
64.
JoyTRHegeleRA. The failure of torcetrapib: what have we learned?Br J Pharmacol2008; 154: 1379–81..
65.
DienerH-CLeesKRLydenPGrottaJDavalosADavisSMShuaibAAshwoodTWasiewskiWAlderferVHardemarkHGRodichokL. NXY-059 for the treatment of acute stroke – pooled analysis of the SAINT I and II trials. Stroke2008; 39: 1751–8.
66.
EronduNGantzIMusserBSuryawanshiSMallickMAddyCCoteJBrayGFujiokaKBaysHHollanderPSanabria-BohorquezSMEngWLangstromBHargreavesRJBurnsHDKanataniAFukamiTMacNeilDJGottesdienerKMAmatrudaJMKaufmanKDHeymsfieldSB. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell Metabol2006; 4: 275–82.
67.
KolaILandisJ. Can the pharmaceutical industry reduce attrition rates?Nat Rev Drug Discov2004; 3: 711–5..
68.
AnsonBDKolajaKLKampTJ. Opportunities for use of human iPS cells in predictive toxicology. Clin Pharmacol Therap2011; 89: 754–8.
69.
KhanJMLyonARHardingSE. The case for induced pluripotent stem cell-derived cardiomyocytes in pharmacological screening. Br J Pharmacol2013; 169: 304–17.
70.
HayashiKShimizuMInoHYamaguchiMTeraiHHoshiNHigashidaHTerashimaNUnoYKanayaHMabuchiH. Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG. Clin Sci2004; 107: 175–82.
71.
BellocqCWildersRSchottJJLouerat-OriouBBoisseauPLe MarecHEscandeDBaroI. A common antitussive drug, clobutinol, precipitates the long QT syndrome 2. Mol Pharmacol2004; 66: 1093–102.
72.
ChevalierPBellocqCMillatGPiquerasEPotetFSchottJJBaroILemarecHBarhaninJRoussonRRodriguez-LafrasseC. Torsades de pointes complicating atrioventricular block: Evidence for a genetic predisposition. Heart Rhythm2007; 4: 170–4.
73.
YangPKankiHDroletBYangTWeiJViswanathanPCHohnloserSHShimizuWSchwartzPJStantonMMurrayKTNorrisKGeorgeALRodenDM. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation2002; 105: 1943–8.
74.
LahtiALKujalaVJChapmanHKoivistoAPPekkanen-MattilaMKerkelaEHyttinenJKontulaKSwanHConklinBRYamanakaSSilvennoinenOAalto-SetalaK. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Model Mech2012; 5: 220–30.
75.
GrskovicMJavaherianAStruloviciBDaleyGQ. Induced pluripotent stem cells – opportunities for disease modelling and drug discovery. Nat Rev Drug Discov2011; 10: 915–29.
76.
KraushaarUMeyerTHessDGepsteinLMummeryCLBraamSRGuentherE. Cardiac safety pharmacology: from human ether-a-go-go related gene channel block towards induced pluripotent stem cell based disease models. Expert opinion on drug safety2012; 11(2): 285–98.
77.
MossAJSchwartzPJCramptonRSTzivoniDLocatiEHMaccluerJHallWJWeitkampLVincentGMGarsonARobinsonJIBenhorinJChoiSS. The long QT syndrome-prospective longitudinal-study of 328 families. Circulation1991; 84: 1136–44.
78.
SchwartzPJLocatiE. The idiopathic long QT syndrome – pathogenetic mechanisms and therapy. Eur Heart J1985; 6: 103–14.
79.
MossAJZarebaWHallWJSchwartzPJCramptonRSBenhorinJVincentGMLocatiEHPrioriSGNapolitanoCMedinaAZhangLRobinsonJLTimothyKTowbinJAAndrewsML. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation2000; 101: 616–23.
80.
GoelAKBergerSPelechADhalaA. Implantable cardioverter defibrillator therapy in children with long QT syndrome. Pediatr Cardiol2004; 25: 370–8.
81.
SchwartzPJSpazzoliniCPrioriSGCrottiLVicentiniALandolinaMGaspariniMWildeAAMKnopsREDenjoyIToivonenLMonnigGAl-FayyadhMJordaensLBorggrefeMHolmgrenCBrugadaPDe RoyLHohnloserSHBrinkPA. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them? Data from the European long-QT syndrome implantable cardioverter-defibrillator (LQTS ICD) registry. Circulation2010; 122: 1272–82.
82.
EbertADYuJRoseFFJrMattisVBLorsonCLThomsonJASvendsenCN. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature2009; 457: 277–80.
83.
HannaJWernigMMarkoulakiSSunCWMeissnerACassadyJPBeardCBrambrinkTWuLCTownesTMJaenischR. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science2007; 318: 1920–3.
84.
XuDAlipioZFinkLMAdcockDMYangJWardDCet XuDAlipioZFinkLMAdcockDMYangJCWardDCMaYP. Phenotypic correction of murine hemophilia A using an iPS cell-based therapy. Proc Natl Acad Sci U S A2009; 106: 808–13.
LianQChowYEstebanMAPeiDTseH-F. Future perspective of induced pluripotent stem cells for diagnosis, drug screening and treatment of human diseases. Thromb Haemost2010; 104: 39–44.
87.
LiWLiKWeiWDingS. Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell2013; 13: 270–83.
88.
OtsujiTGMinamiIKuroseYYamauchiKTadaMNakatsujiN. Progressive maturation in contracting cardiomyocytes derived from human embryonic stem cells: Qualitative effects on electrophysiological responses to drugs. Stem Cell Res2010; 4: 201–13.
89.
TakebeTSekineKEnomuraMKoikeHKimuraMOgaeriTZhangRRUenoYZhengYWKoikeNAoyamaSAdachiYTaniguchiH. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature2013; 499: 481–4.
90.
MaherB. How to build a heart. Nature2013; 499: 20–2.
91.
Kyodo. Japanese Government Panel OKs World’s First Clinical Research Using iPS Cells. See http://www.japantimes.co.jp/news/2013/06/27/national/j apanese-government-panel-oks-worlds-first-clinical-research-using-ips-cells/(last checked 27 June 2013.).
