Skip to main content

Generation and Application of Human Pluripotent Stem Cell-Derived Cardiomyocytes

  • Chapter
  • First Online:
Cardiac Regeneration

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 4))

  • 881 Accesses

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful technology with established applications in regenerative medicine, disease modeling, drug testing and discovery, and developmental biology. The in vitro generation of human cardiomyocytes has progressed rapidly over the last 15 years, and cardiac differentiation of human pluripotent stem cells (hPSC) is now a simple and routine process for many laboratories, generating contracting fetal-like cardiomyocytes that recapitulate a variety of known cardiovascular disease phenotypes. Here we discuss the history and existing knowledge in the field on the generation of cardiomyocytes from human pluripotent stem cells. We cover the potential clinical and investigational applications of hPSC-CMs, as well as the role of the pluripotent state in differentiation, and current methodologies for differentiation, purification, directed cardiomyocyte subtype specification and maturation, and large-scale production. We conclude with a discussion on the future of the field.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

References

  • Aguilar JS, Begum AN, Alvarez J, Zhang XB, Hong Y, Hao J (2015) Directed cardiomyogenesis of human pluripotent stem cells by modulating Wnt/beta-catenin and BMP signalling with small molecules. Biochem J 469(2):235–241

    Article  CAS  PubMed  Google Scholar 

  • Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA (2000) Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 227(2):271–278

    Article  CAS  PubMed  Google Scholar 

  • Amit M, Shariki C, Margulets V, Itskovitz-Eldor J (2004) Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod 70(3):837–845

    Article  CAS  PubMed  Google Scholar 

  • Anderson D, Self T, Mellor IR, Goh G, Hill SJ, Denning C (2007) Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol Ther 15(11):2027–2036

    Article  CAS  PubMed  Google Scholar 

  • Barbuti A, Robinson RB (2015) Stem cell-derived nodal-like cardiomyocytes as a novel pharmacologic tool: insights from sinoatrial node development and function. Pharmacol Rev 67(2):368–388

    Article  CAS  PubMed  Google Scholar 

  • Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, Quaini F, Sonnenblick EH, Olivetti G, Anversa P (1994) Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 89(1):151–163

    Article  CAS  PubMed  Google Scholar 

  • van den Berg CW, Elliott DA, Braam SR, Mummery CL, Davis RP (2016) Differentiation of human pluripotent stem cells to cardiomyocytes under defined conditions. Methods Mol Biol 1353:163–180

    Article  PubMed  CAS  Google Scholar 

  • Bernemann C, Greber B, Ko K, Sterneckert J, Han DW, Arauzo-Bravo MJ, Scholer HR (2011) Distinct developmental ground states of epiblast stem cell lines determine different pluripotency features. Stem Cells 29(10):1496–1503

    Article  CAS  PubMed  Google Scholar 

  • Birket MJ, Ribeiro MC, Kosmidis G, Ward D, Leitoguinho AR, van de Pol V, Dambrot C, Devalla HD, Davis RP, Mastroberardino PG, Atsma DE, Passier R, Mummery CL (2015a) Contractile defect caused by mutation in MYBPC3 revealed under conditions optimized for human PSC-cardiomyocyte function. Cell Rep 13(4):733–745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Birket MJ, Ribeiro MC, Verkerk AO, Ward D, Leitoguinho AR, den Hartogh SC, Orlova VV, Devalla HD, Schwach V, Bellin M, Passier R, Mummery CL (2015b) Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells. Nat Biotechnol 33(9):970–979

    Article  CAS  PubMed  Google Scholar 

  • Bizy A, Guerrero-Serna G, Hu B, Ponce-Balbuena D, Willis BC, Zarzoso M, Ramirez RJ, Sener MF, Mundada LV, Klos M, Devaney EJ, Vikstrom KL, Herron TJ, Jalife J (2013) Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes. Stem Cell Res 11(3):1335–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blakeley P, Fogarty NM, del Valle I, Wamaitha SE, Hu TX, Elder K, Snell P, Christie L, Robson P, Niakan KK (2015) Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development 142(18):3151–3165

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bolli R, Tang XL, Sanganalmath SK, Rimoldi O, Mosna F, Abdel-Latif A, Jneid H, Rota M, Leri A, Kajstura J (2013) Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 128(2):122–131

    Article  CAS  PubMed  Google Scholar 

  • Brade T, Pane LS, Moretti A, Chien KR, Laugwitz KL (2013) Embryonic heart progenitors and cardiogenesis. Cold Spring Harb Perspect Med 3(10):a013847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brons IG, Smithers LE, Trotter MW, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM, Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA, Vallier L (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448(7150):191–195

    Article  CAS  PubMed  Google Scholar 

  • Broughton KM, Sussman MA (2016) Empowering adult stem cells for myocardial regeneration V2.0: success in small steps. Circ Res 118(5):867–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burridge PW, Anderson D, Priddle H, Barbadillo Munoz MD, Chamberlain S, Allegrucci C, Young LE, Denning C (2007) Improved human embryonic stem cell embryoid body homogeneity and cardiomyocyte differentiation from a novel V-96 plate aggregation system highlights interline variability. Stem Cells 25(4):929–938

    Article  CAS  PubMed  Google Scholar 

  • Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, Mahairaki V, Koliatsos VE, Tung L, Zambidis ET (2011) A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS One 6(4):e18293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burridge PW, Keller G, Gold JD, Wu JC (2012) Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 10(1):16–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, Lan F, Diecke S, Huber B, Mordwinkin NM, Plews JR, Abilez OJ, Cui B, Gold JD, Wu JC (2014) Chemically defined generation of human cardiomyocytes. Nat Methods 11(8):855–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burridge PW, Li YF, Matsa E, Wu H, Ong SG, Sharma A, Holmstrom A, Chang AC, Coronado MJ, Ebert AD, Knowles JW, Telli ML, Witteles RM, Blau HM, Bernstein D, Altman RB, Wu JC (2016) Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22(5):547–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cahan P, Daley GQ (2013) Origins and implications of pluripotent stem cell variability and heterogeneity. Nat Rev Mol Cell Biol 14(6):357–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao N, Liu Z, Chen Z, Wang J, Chen T, Zhao X, Ma Y, Qin L, Kang J, Wei B, Wang L, Jin Y, Yang HT (2012) Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells. Cell Res 22(1):219–236

    Article  CAS  PubMed  Google Scholar 

  • Cao N, Liang H, Huang J, Wang J, Chen Y, Chen Z, Yang HT (2013) Highly efficient induction and long-term maintenance of multipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions. Cell Res 23(9):1119–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpenter L, Carr C, Yang CT, Stuckey DJ, Clarke K, Watt SM (2012) Efficient differentiation of human induced pluripotent stem cells generates cardiac cells that provide protection following myocardial infarction in the rat. Stem Cells Dev 21(6):977–986

    Article  CAS  PubMed  Google Scholar 

  • Carter MG, Smagghe BJ, Stewart AK, Rapley JA, Lynch E, Bernier KJ, Keating KW, Hatziioannou VM, Hartman EJ, Bamdad CC (2016) A primitive growth factor, NME7AB, is sufficient to induce stable naive state human pluripotency; reprogramming in this novel growth factor confers superior differentiation. Stem Cells 34(4):847–859

    Article  CAS  PubMed  Google Scholar 

  • Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, Smuga-Otto K, Howden SE, Diol NR, Propson NE, Wagner R, Lee GO, Antosiewicz-Bourget J, Teng JM, Thomson JA (2011) Chemically defined conditions for human iPSC derivation and culture. Nat Methods 8(5):424–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen VC, Couture SM, Ye J, Lin Z, Hua G, Huang HI, Wu J, Hsu D, Carpenter MK, Couture LA (2012) Scalable GMP compliant suspension culture system for human ES cells. Stem Cell Res 8(3):388–402

    Article  CAS  PubMed  Google Scholar 

  • Chen VC, Ye J, Shukla P, Hua G, Chen D, Lin Z, Liu JC, Chai J, Gold J, Wu J, Hsu D, Couture LA (2015) Development of a scalable suspension culture for cardiac differentiation from human pluripotent stem cells. Stem Cell Res 15(2):365–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ, Gantz JA, Fugate JA, Muskheli V, Gough GM, Vogel KW, Astley CA, Hotchkiss CE, Baldessari A, Pabon L, Reinecke H, Gill EA, Nelson V, Kiem HP, Laflamme MA, Murry CE (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510(7504):273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chuva de Sousa Lopes SM, Hassink RJ, Feijen A, van Rooijen MA, Doevendans PA, Tertoolen L, Brutel de la Riviere A, Mummery CL (2006) Patterning the heart, a template for human cardiomyocyte development. Dev Dyn 235(7):1994–2002

    Article  PubMed  Google Scholar 

  • Danker T, Moller C (2014) Early identification of hERG liability in drug discovery programs by automated patch clamp. Front Pharmacol 5:203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Los AA, Loh YH, Tesar PJ, Daley GQ (2012) Accessing naive human pluripotency. Curr Opin Genet Dev 22(3):272–282

    Article  CAS  Google Scholar 

  • Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, Jackson C, Gkatzis K, Elliott DA, Chuva de Sousa Lopes SM, Mummery CL, Verkerk AO, Passier R (2015) Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology. EMBO Mol Med 7(4):394–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Pasquale E, Lodola F, Miragoli M, Denegri M, Avelino-Cruz JE, Buonocore M, Nakahama H, Portararo P, Bloise R, Napolitano C, Condorelli G, Priori SG (2013) CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia. Cell Death Dis 4:e843

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dick E, Kalra S, Anderson D, George V, Ritson M, Laval S, Barresi R, Aartsma-Rus A, Lochmuller H, Denning C (2013) Exon skipping and gene transfer restore dystrophin expression in hiPSC-cardiomyocytes harbouring DMD mutations. Stem Cells Dev 22(20):2714–2724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DiMasi JA, Feldman L, Seckler A, Wilson A (2010) Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther 87(3):272–277

    Article  CAS  PubMed  Google Scholar 

  • Dixon JE, Dick E, Rajamohan D, Shakesheff KM, Denning C (2011) Directed differentiation of human embryonic stem cells to interrogate the cardiac gene regulatory network. Mol Ther 19(9):1695–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drawnel FM, Boccardo S, Prummer M, Delobel F, Graff A, Weber M, Gerard R, Badi L, Kam-Thong T, Bu L, Jiang X, Hoflack JC, Kiialainen A, Jeworutzki E, Aoyama N, Carlson C, Burcin M, Gromo G, Boehringer M, Stahlberg H, Hall BJ, Magnone MC, Kolaja K, Chien KR, Bailly J, Iacone R (2014) Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep 9(3):810–821

    Article  CAS  PubMed  Google Scholar 

  • Du DT, Hellen N, Kane C, Terracciano CM (2015) Action potential morphology of human induced pluripotent stem cell-derived cardiomyocytes does not predict cardiac chamber specificity and is dependent on cell density. Biophys J 108(1):1–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dubois NC, Craft AM, Sharma P, Elliott DA, Stanley EG, Elefanty AG, Gramolini A, Keller G (2011) SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat Biotechnol 29(11):1011–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egashira T, Yuasa S, Suzuki T, Aizawa Y, Yamakawa H, Matsuhashi T, Ohno Y, Tohyama S, Okata S, Seki T, Kuroda Y, Yae K, Hashimoto H, Tanaka T, Hattori F, Sato T, Miyoshi S, Takatsuki S, Murata M, Kurokawa J, Furukawa T, Makita N, Aiba T, Shimizu W, Horie M, Kamiya K, Kodama I, Ogawa S, Fukuda K (2012) Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovasc Res 95(4):419–429

    Article  CAS  PubMed  Google Scholar 

  • Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL, Biben C, Hatzistavrou T, Hirst CE, Yu QC, Skelton RJ, Ward-van Oostwaard D, Lim SM, Khammy O, Li X, Hawes SM, Davis RP, Goulburn AL, Passier R, Prall OW, Haynes JM, Pouton CW, Kaye DM, Mummery CL, Elefanty AG, Stanley EG (2011) NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods 8(12):1037–1040

    Article  CAS  PubMed  Google Scholar 

  • Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156

    Article  CAS  PubMed  Google Scholar 

  • Fatima A, Xu G, Shao K, Papadopoulos S, Lehmann M, Arnaiz-Cot JJ, Rosa AO, Nguemo F, Matzkies M, Dittmann S, Stone SL, Linke M, Zechner U, Beyer V, Hennies HC, Rosenkranz S, Klauke B, Parwani AS, Haverkamp W, Pfitzer G, Farr M, Cleemann L, Morad M, Milting H, Hescheler J, Saric T (2011) In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cell Physiol Biochem 28(4):579–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fatima A, Kaifeng S, Dittmann S, Xu G, Gupta MK, Linke M, Zechner U, Nguemo F, Milting H, Farr M, Hescheler J, Saric T (2013) The disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long QT syndrome type 3 patients. PLoS One 8(12):e83005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feaster TK, Cadar AG, Wang L, Williams CH, Chun YW, Hempel JE, Bloodworth N, Merryman WD, Lim CC, Wu JC, Knollmann BC, Hong CC (2015) Matrigel mattress: a method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circ Res 117(12):995–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fermini B, Hancox JC, Abi-Gerges N, Bridgland-Taylor M, Chaudhary KW, Colatsky T, Correll K, Crumb W, Damiano B, Erdemli G, Gintant G, Imredy J, Koerner J, Kramer J, Levesque P, Li Z, Lindqvist A, Obejero-Paz CA, Rampe D, Sawada K, Strauss DG, Vandenberg JI (2016) A new perspective in the field of cardiac safety testing through the comprehensive in vitro proarrhythmia assay paradigm. J Biomol Screen 21(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Fonoudi H, Yeganeh M, Fattahi F, Ghazizadeh Z, Rassouli H, Alikhani M, Mojarad BA, Baharvand H, Salekdeh GH, Aghdami N (2013) ISL1 protein transduction promotes cardiomyocyte differentiation from human embryonic stem cells. PLoS One 8(1):e55577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frank S, Zhang M, Scholer HR, Greber B (2012) Small molecule-assisted, line-independent maintenance of human pluripotent stem cells in defined conditions. PLoS One 7(7):e41958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85(8):348–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gafni O, Weinberger L, Mansour AA, Manor YS, Chomsky E, Ben-Yosef D, Kalma Y, Viukov S, Maza I, Zviran A, Rais Y, Shipony Z, Mukamel Z, Krupalnik V, Zerbib M, Geula S, Caspi I, Schneir D, Shwartz T, Gilad S, Amann-Zalcenstein D, Benjamin S, Amit I, Tanay A, Massarwa R, Novershtern N, Hanna JH (2013) Derivation of novel human ground state naive pluripotent stem cells. Nature 504(7479):282–286

    Article  CAS  PubMed  Google Scholar 

  • Gallina C, Turinetto V, Giachino C (2015) A new paradigm in cardiac regeneration: the mesenchymal stem cell secretome. Stem Cells Int 2015:765846

    Article  PubMed  PubMed Central  Google Scholar 

  • Gessert S, Kuhl M (2010) The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ Res 107(2):186–199

    Article  CAS  PubMed  Google Scholar 

  • Gomes Fernandes M, Dries R, Roost MS, Semrau S, de Melo BA, Davis RP, Ramakrishnan R, Szuhai K, Maas E, Umans L, Abon Escalona V, Salvatori D, Deforce D, Van Criekinge W, Huylebroeck D, Mummery C, Zwijsen A, Chuva de Sousa Lopes SM (2016) BMP-SMAD signaling regulates lineage priming, but is dispensable for self-renewal in mouse embryonic stem cells. Stem Cell Rep 6(1):85–94

    Article  CAS  Google Scholar 

  • Gonzalez R, Lee JW, Schultz PG (2011) Stepwise chemically induced cardiomyocyte specification of human embryonic stem cells. Angew Chem 50(47):11181–11185

    Article  CAS  Google Scholar 

  • Graichen R, Xu X, Braam SR, Balakrishnan T, Norfiza S, Sieh S, Soo SY, Tham SC, Mummery C, Colman A, Zweigerdt R, Davidson BP (2008) Enhanced cardiomyogenesis of human embryonic stem cells by a small molecular inhibitor of p38 MAPK. Differentiation 76(4):357–370

    Article  CAS  PubMed  Google Scholar 

  • Guan X, Mack DL, Moreno CM, Strande JL, Mathieu J, Shi Y, Markert CD, Wang Z, Liu G, Lawlor MW, Moorefield EC, Jones TN, Fugate JA, Furth ME, Murry CE, Ruohola-Baker H, Zhang Y, Santana LF, Childers MK (2014) Dystrophin-deficient cardiomyocytes derived from human urine: new biologic reagents for drug discovery. Stem Cell Res 12(2):467–480

    Article  CAS  PubMed  Google Scholar 

  • Guo G, von Meyenn F, Santos F, Chen Y, Reik W, Bertone P, Smith A, Nichols J (2016) Naive pluripotent stem cells derived directly from isolated cells of the human inner cell mass. Stem Cell Rep 6(4):437–446

    Article  CAS  Google Scholar 

  • Han L, Li Y, Tchao J, Kaplan AD, Lin B, Li Y, Mich-Basso J, Lis A, Hassan N, London B, Bett GC, Tobita K, Rasmusson RL, Yang L (2014) Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells. Cardiovasc Res 104(2):258–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanna J, Cheng AW, Saha K, Kim J, Lengner CJ, Soldner F, Cassady JP, Muffat J, Carey BW, Jaenisch R (2010) Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci U S A 107(20):9222–9227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartung S, Schwanke K, Haase A, David R, Franz WM, Martin U, Zweigerdt R (2013) Directing cardiomyogenic differentiation of human pluripotent stem cells by plasmid-based transient overexpression of cardiac transcription factors. Stem Cells Dev 22(7):1112–1125

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto A, Naito AT, Lee JK, Kitazume-Taneike R, Ito M, Yamaguchi T, Nakata R, Sumida T, Okada K, Nakagawa A, Higo T, Kuramoto Y, Sakai T, Tominaga K, Okinaga T, Kogaki S, Ozono K, Miyagawa S, Sawa Y, Sakata Y, Morita H, Umezawa A, Komuro I (2016) Generation of induced pluripotent stem cells from patients with duchenne muscular dystrophy and their induction to cardiomyocytes. Int Heart J 57(1):112–117

    Article  CAS  PubMed  Google Scholar 

  • Hattori F, Chen H, Yamashita H, Tohyama S, Satoh YS, Yuasa S, Li W, Yamakawa H, Tanaka T, Onitsuka T, Shimoji K, Ohno Y, Egashira T, Kaneda R, Murata M, Hidaka K, Morisaki T, Sasaki E, Suzuki T, Sano M, Makino S, Oikawa S, Fukuda K (2010) Nongenetic method for purifying stem cell-derived cardiomyocytes. Nat Methods 7(1):61–66

    Article  CAS  PubMed  Google Scholar 

  • Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE, Dulce R, Pattany PM, Valdes D, Revilla C, Heldman AW, McNiece I, Hare JM (2010) Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 107(7):913–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hemmi N, Tohyama S, Nakajima K, Kanazawa H, Suzuki T, Hattori F, Seki T, Kishino Y, Hirano A, Okada M, Tabei R, Ohno R, Fujita C, Haruna T, Yuasa S, Sano M, Fujita J, Fukuda K (2014) A massive suspension culture system with metabolic purification for human pluripotent stem cell-derived cardiomyocytes. Stem Cells Transl Med 3(12):1473–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herron TJ, Rocha AM, Campbell KF, Ponce-Balbuena D, Willis BC, Guerrero-Serna G, Liu Q, Klos M, Musa H, Zarzoso M, Bizy A, Furness J, Anumonwo J, Mironov S, Jalife J (2016) Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function. Circ Arrhythm Electrophysiol 9(4)

    Google Scholar 

  • Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, Gorham J, Yang L, Schafer S, Sheng CC, Haghighi A, Homsy J, Hubner N, Church G, Cook SA, Linke WA, Chen CS, Seidman JG, Seidman CE (2015) HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349(6251):982–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang HP, Chen PH, Hwu WL, Chuang CY, Chien YH, Stone L, Chien CL, Li LT, Chiang SC, Chen HF, Ho HN, Chen CH, Kuo HC (2011) Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification. Hum Mol Genet 20(24):4851–4864

    Article  CAS  PubMed  Google Scholar 

  • Hudson J, Titmarsh D, Hidalgo A, Wolvetang E, Cooper-White J (2012) Primitive cardiac cells from human embryonic stem cells. Stem Cells Dev 21(9):1513–1523

    Article  CAS  PubMed  Google Scholar 

  • Ionta V, Liang W, Kim EH, Rafie R, Giacomello A, Marban E, Cho HC (2015) SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. Stem Cell Reports 4(1):129–142

    Article  CAS  PubMed  Google Scholar 

  • Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M, Soreq H, Benvenisty N (2000) Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med 6(2):88–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, Arbel G, Hammerman H, Boulos M, Gepstein L (2011) Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471(7337):225–229

    Article  CAS  PubMed  Google Scholar 

  • Itzhaki I, Maizels L, Huber I, Gepstein A, Arbel G, Caspi O, Miller L, Belhassen B, Nof E, Glikson M, Gepstein L (2012) Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J Am Coll Cardiol 60(11):990–1000

    Article  CAS  PubMed  Google Scholar 

  • Ivashchenko CY, Pipes GC, Lozinskaya IM, Lin Z, Xiaoping X, Needle S, Grygielko ET, Hu E, Toomey JR, Lepore JJ, Willette RN (2013) Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype. Am J Physiol Heart Circ Physiol 305(6):H913–H922

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Habibollah S, Tilgner K, Collin J, Barta T, Al-Aama JY, Tesarov L, Hussain R, Trafford AW, Kirkwood G, Sernagor E, Eleftheriou CG, Przyborski S, Stojkovic M, Lako M, Keavney B, Armstrong L (2014) An induced pluripotent stem cell model of hypoplastic left heart syndrome (HLHS) reveals multiple expression and functional differences in HLHS-derived cardiac myocytes. Stem Cells Transl Med 3(4):416–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston PV, Sasano T, Mills K, Evers R, Lee ST, Smith RR, Lardo AC, Lai S, Steenbergen C, Gerstenblith G, Lange R, Marban E (2009) Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120(12):1075–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Josowitz R, Lu J, Falce C, D’Souza SL, Wu M, Cohen N, Dubois NC, Zhao Y, Sobie EA, Fishman GI, Gelb BD (2014) Identification and purification of human induced pluripotent stem cell-derived atrial-like cardiomyocytes based on sarcolipin expression. PLoS One 9(7):e101316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jouni M, Si-Tayeb K, Es-Salah-Lamoureux Z, Latypova X, Champon B, Caillaud A, Rungoat A, Charpentier F, Loussouarn G, Baro I, Zibara K, Lemarchand P, Gaborit N (2015) Toward personalized medicine: using cardiomyocytes differentiated from urine-derived pluripotent stem cells to recapitulate electrophysiological characteristics of type 2 long QT syndrome. J Am Heart Assoc 4(9):e002159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jung CB, Moretti A, Mederos Y, Schnitzler M, Iop L, Storch U, Bellin M, Dorn T, Ruppenthal S, Pfeiffer S, Goedel A, Dirschinger RJ, Seyfarth M, Lam JT, Sinnecker D, Gudermann T, Lipp P, Laugwitz KL (2012) Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med 4(3):180–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung JJ, Husse B, Rimmbach C, Krebs S, Stieber J, Steinhoff G, Dendorfer A, Franz WM, David R (2014) Programming and isolation of highly pure physiologically and pharmacologically functional sinus-nodal bodies from pluripotent stem cells. Stem Cell Rep 2(5):592–605

    Article  Google Scholar 

  • Kaitin KI (2010) Deconstructing the drug development process: the new face of innovation. Clin Pharmacol Ther 87(3):356–361

    Article  CAS  PubMed  Google Scholar 

  • Kane C, Du DT, Hellen N, Terracciano CM (2016) The fallacy of assigning chamber specificity to iPSC cardiac myocytes from action potential morphology. Biophys J 110(1):281–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karakikes I, Stillitano F, Nonnenmacher M, Tzimas C, Sanoudou D, Termglinchan V, Kong CW, Rushing S, Hansen J, Ceholski D, Kolokathis F, Kremastinos D, Katoulis A, Ren L, Cohen N, Gho JM, Tsiapras D, Vink A, Wu JC, Asselbergs FW, Li RA, Hulot JS, Kranias EG, Hajjar RJ (2015) Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun 6:6955

    Article  CAS  PubMed  Google Scholar 

  • Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, Ellis J, Keller G (2011) Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8(2):228–240

    Article  CAS  PubMed  Google Scholar 

  • Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, Livne E, Binah O, Itskovitz-Eldor J, Gepstein L (2001) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Investig 108(3):407–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, Huber I, Satin J, Itskovitz-Eldor J, Gepstein L (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22(10):1282–1289

    Article  CAS  PubMed  Google Scholar 

  • Kelly RG (2012) The second heart field. Curr Top Dev Biol 100:33–65

    Article  CAS  PubMed  Google Scholar 

  • Kempf H, Olmer R, Kropp C, Ruckert M, Jara-Avaca M, Robles-Diaz D, Franke A, Elliott DA, Wojciechowski D, Fischer M, Roa Lara A, Kensah G, Gruh I, Haverich A, Martin U, Zweigerdt R (2014) Controlling expansion and cardiomyogenic differentiation of human pluripotent stem cells in scalable suspension culture. Stem Cell Reports 3(6):1132–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kempf H, Kropp C, Olmer R, Martin U, Zweigerdt R (2015) Cardiac differentiation of human pluripotent stem cells in scalable suspension culture. Nat Protoc 10(9):1345–1361

    Article  CAS  PubMed  Google Scholar 

  • Kempf H, Andree B, Zweigerdt R (2016) Large-scale production of human pluripotent stem cell derived cardiomyocytes. Adv Drug Deliv Rev 96:18–30

    Article  CAS  PubMed  Google Scholar 

  • Khanabdali R, Rosdah AA, Dusting GJ, Lim SY (2016) Harnessing the secretome of cardiac stem cells as therapy for ischemic heart disease. Biochem Pharmacol 113:1–11

    Article  CAS  PubMed  Google Scholar 

  • Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S, Kan NG, Forcales S, Puri PL, Leone TC, Marine JE, Calkins H, Kelly DP, Judge DP, Chen HS (2013) Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature 494(7435):105–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimelman D (2006) Mesoderm induction: from caps to chips. Nat Rev Genet 7(5):360–372

    Article  CAS  PubMed  Google Scholar 

  • Kita-Matsuo H, Barcova M, Prigozhina N, Salomonis N, Wei K, Jacot JG, Nelson B, Spiering S, Haverslag R, Kim C, Talantova M, Bajpai R, Calzolari D, Terskikh A, McCulloch AD, Price JH, Conklin BR, Chen HS, Mercola M (2009) Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes. PLoS One 4(4):e5046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kobayashi J, Yoshida M, Tarui S, Hirata M, Nagai Y, Kasahara S, Naruse K, Ito H, Sano S, Oh H (2014) Directed differentiation of patient-specific induced pluripotent stem cells identifies the transcriptional repression and epigenetic modification of NKX2-5, HAND1, and NOTCH1 in hypoplastic left heart syndrome. PLoS One 9(7):e102796

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kosmidis G, Bellin M, Ribeiro MC, van Meer B, Ward-van Oostwaard D, Passier R, Tertoolen LG, Mummery CL, Casini S (2015) Altered calcium handling and increased contraction force in human embryonic stem cell derived cardiomyocytes following short term dexamethasone exposure. Biochem Biophys Res Commun 467(4):998–1005

    Article  CAS  PubMed  Google Scholar 

  • Kujala K, Paavola J, Lahti A, Larsson K, Pekkanen-Mattila M, Viitasalo M, Lahtinen AM, Toivonen L, Kontula K, Swan H, Laine M, Silvennoinen O, Aalto-Setala K (2012) Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS One 7(9):e44660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar N, Richter J, Cutts J, Bush KT, Trujillo C, Nigam SK, Gaasterland T, Brafman D, Willert K (2015) Generation of an expandable intermediate mesoderm restricted progenitor cell line from human pluripotent stem cells. elife 4:e08413

    Article  PubMed  PubMed Central  Google Scholar 

  • Kwon C, Qian L, Cheng P, Nigam V, Arnold J, Srivastava D (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11(8):951–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S, O'Sullivan C, Collins L, Chen Y, Minami E, Gill EA, Ueno S, Yuan C, Gold J, Murry CE (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25(9):1015–1024

    Article  CAS  PubMed  Google Scholar 

  • Lahti AL, Kujala VJ, Chapman H, Koivisto AP, Pekkanen-Mattila M, Kerkela E, Hyttinen J, Kontula K, Swan H, Conklin BR, Yamanaka S, Silvennoinen O, Aalto-Setala K (2012) Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Model Mech 5(2):220–230

    Article  CAS  PubMed  Google Scholar 

  • Lalit PA, Salick MR, Nelson DO, Squirrell JM, Shafer CM, Patel NG, Saeed I, Schmuck EG, Markandeya YS, Wong R, Lea MR, Eliceiri KW, Hacker TA, Crone WC, Kyba M, Garry DJ, Stewart R, Thomson JA, Downs KM, Lyons GE, Kamp TJ (2016) Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors. Cell Stem Cell 18(3):354–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lam AT, Chen AK, Li J, Birch WR, Reuveny S, Oh SK (2014) Conjoint propagation and differentiation of human embryonic stem cells to cardiomyocytes in a defined microcarrier spinner culture. Stem Cell Res Ther 5(5):110

    Article  PubMed  PubMed Central  Google Scholar 

  • Lam AT, Chen AK, Ting SQ, Reuveny S, Oh SK (2016) Integrated processes for expansion and differentiation of human pluripotent stem cells in suspended microcarriers cultures. Biochem Biophys Res Commun 473(3):764–768

    Article  CAS  PubMed  Google Scholar 

  • Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, Han L, Yen M, Wang Y, Sun N, Abilez OJ, Hu S, Ebert AD, Navarrete EG, Simmons CS, Wheeler M, Pruitt B, Lewis R, Yamaguchi Y, Ashley EA, Bers DM, Robbins RC, Longaker MT, Wu JC (2013) Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell 12(1):101–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leahy A, Xiong JW, Kuhnert F, Stuhlmann H (1999) Use of developmental marker genes to define temporal and spatial patterns of differentiation during embryoid body formation. J Exp Zool 284(1):67–81

    Article  CAS  PubMed  Google Scholar 

  • Lecina M, Ting S, Choo A, Reuveny S, Oh S (2010) Scalable platform for human embryonic stem cell differentiation to cardiomyocytes in suspended microcarrier cultures. Tissue Eng Part C Methods 16(6):1609–1619

    Article  CAS  PubMed  Google Scholar 

  • Lee YK, Ng KM, Lai WH, Chan YC, Lau YM, Lian Q, Tse HF, Siu CW (2011) Calcium homeostasis in human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Rev 7(4):976–986

    Article  CAS  PubMed Central  Google Scholar 

  • Leiker M, Suzuki G, Iyer VS, Canty JM Jr, Lee T (2008) Assessment of a nuclear affinity labeling method for tracking implanted mesenchymal stem cells. Cell Transplant 17(8):911–922

    Article  PubMed  Google Scholar 

  • Li Y, Powell S, Brunette E, Lebkowski J, Mandalam R (2005) Expansion of human embryonic stem cells in defined serum-free medium devoid of animal-derived products. Biotechnol Bioeng 91(6):688–698

    Article  CAS  PubMed  Google Scholar 

  • Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, Raval KK, Zhang J, Kamp TJ, Palecek SP (2012) Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A 109(27):E1848–E1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lian X, Zhang J, Azarin SM, Zhu K, Hazeltine LB, Bao X, Hsiao C, Kamp TJ, Palecek SP (2013) Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions. Nat Protoc 8(1):162–175

    Article  CAS  PubMed  Google Scholar 

  • Lian X, Bao X, Zilberter M, Westman M, Fisahn A, Hsiao C, Hazeltine LB, Dunn KK, Kamp TJ, Palecek SP (2015) Chemically defined, albumin-free human cardiomyocyte generation. Nat Methods 12(7):595–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang P, Lan F, Lee AS, Gong T, Sanchez-Freire V, Wang Y, Diecke S, Sallam K, Knowles JW, Wang PJ, Nguyen PK, Bers DM, Robbins RC, Wu JC (2013) Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation 127(16):1677–1691

    Article  CAS  PubMed  Google Scholar 

  • Lieu DK, Fu JD, Chiamvimonvat N, Tung KC, McNerney GP, Huser T, Keller G, Kong CW, Li RA (2013) Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol 6(1):191–201

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin B, Li Y, Han L, Kaplan AD, Ao Y, Kalra S, Bett GC, Rasmusson RL, Denning C, Yang L (2015) Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. Dis Model Mech 8(5):457–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Y, Linask KL, Mallon B, Johnson K, Klein M, Beers J, Xie W, Du Y, Liu C, Lai Y, Zou J, Haigney M, Yang H, Rao M, Chen G (2016) Heparin promotes cardiac differentiation of human pluripotent stem cells in chemically defined albumin-free medium, enabling consistent manufacture of cardiomyocytes. Stem Cells Transl Med 6(2):527–538

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ludwig TE, Levenstein ME, Jones JM, Berggren WT, Mitchen ER, Frane JL, Crandall LJ, Daigh CA, Conard KR, Piekarczyk MS, Llanas RA, Thomson JA (2006) Derivation of human embryonic stem cells in defined conditions. Nat Biotechnol 24(2):185–187

    Article  CAS  PubMed  Google Scholar 

  • Lundy SD, Zhu WZ, Regnier M, Laflamme MA (2013) Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev 22(14):1991–2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, Kolaja KL, Swanson BJ, January CT (2011) High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol 301(5):H2006–H2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma D, Wei H, Lu J, Ho S, Zhang G, Sun X, Oh Y, Tan SH, Ng ML, Shim W, Wong P, Liew R (2013a) Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 34(15):1122–1133

    Article  CAS  PubMed  Google Scholar 

  • Ma D, Wei H, Zhao Y, Lu J, Li G, Sahib NB, Tan TH, Wong KY, Shim W, Wong P, Cook SA, Liew R (2013b) Modeling type 3 long QT syndrome with cardiomyocytes derived from patient-specific induced pluripotent stem cells. Int J Cardiol 168(6):5277–5286

    Article  PubMed  Google Scholar 

  • Ma D, Wei H, Lu J, Huang D, Liu Z, Loh LJ, Islam O, Liew R, Shim W, Cook SA (2015) Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patient-specific induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther 6:39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1(1):55–70

    Article  CAS  PubMed  Google Scholar 

  • Malan D, Zhang M, Stallmeyer B, Muller J, Fleischmann BK, Schulze-Bahr E, Sasse P, Greber B (2016) Human iPS cell model of type 3 long QT syndrome recapitulates drug-based phenotype correction. Basic Res Cardiol 111(2):14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Marinho PA, Chailangkarn T, Muotri AR (2015) Systematic optimization of human pluripotent stem cells media using design of experiments. Sci Rep 5:9834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsa E, Rajamohan D, Dick E, Young L, Mellor I, Staniforth A, Denning C (2011) Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J 32(8):952–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsa E, Dixon JE, Medway C, Georgiou O, Patel MJ, Morgan K, Kemp PJ, Staniforth A, Mellor I, Denning C (2014) Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. Eur Heart J 35(16):1078–1087

    Article  CAS  PubMed  Google Scholar 

  • Mehta A, Sequiera GL, Ramachandra CJ, Sudibyo Y, Chung Y, Sheng J, Wong KY, Tan TH, Wong P, Liew R, Shim W (2014) Re-trafficking of hERG reverses long QT syndrome 2 phenotype in human iPS-derived cardiomyocytes. Cardiovasc Res 102(3):497–506

    Article  CAS  PubMed  Google Scholar 

  • Minami I, Yamada K, Otsuji TG, Yamamoto T, Shen Y, Otsuka S, Kadota S, Morone N, Barve M, Asai Y, Tenkova-Heuser T, Heuser JE, Uesugi M, Aiba K, Nakatsuji N (2012) A small molecule that promotes cardiac differentiation of human pluripotent stem cells under defined, cytokine- and xeno-free conditions. Cell Rep 2(5):1448–1460

    Article  CAS  PubMed  Google Scholar 

  • Montserrat N, Nivet E, Sancho-Martinez I, Hishida T, Kumar S, Miquel L, Cortina C, Hishida Y, Xia Y, Esteban CR, Izpisua Belmonte JC (2013) Reprogramming of human fibroblasts to pluripotency with lineage specifiers. Cell Stem Cell 13(3):341–350

    Article  CAS  PubMed  Google Scholar 

  • Mordwinkin NM, Burridge PW, Wu JC (2013) A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards. J Cardiovasc Transl Res 6(1):22–30

    Article  PubMed  Google Scholar 

  • Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, Dorn T, Goedel A, Hohnke C, Hofmann F, Seyfarth M, Sinnecker D, Schomig A, Laugwitz KL (2010) Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363(15):1397–1409

    Article  CAS  PubMed  Google Scholar 

  • Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després J-P, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB (2016) Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 133(4):e38–e360

    PubMed  Google Scholar 

  • Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L (2003) Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107(21):2733–2740

    Article  CAS  PubMed  Google Scholar 

  • Murry CE, Reinecke H, Pabon LM (2006) Regeneration gaps: observations on stem cells and cardiac repair. J Am Coll Cardiol 47(9):1777–1785

    Article  PubMed  Google Scholar 

  • Ng ES, Davis RP, Azzola L, Stanley EG, Elefanty AG (2005) Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood 106(5):1601–1603

    Article  CAS  PubMed  Google Scholar 

  • Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4(6):487–492

    Article  CAS  PubMed  Google Scholar 

  • Niebruegge S, Bauwens CL, Peerani R, Thavandiran N, Masse S, Sevaptisidis E, Nanthakumar K, Woodhouse K, Husain M, Kumacheva E, Zandstra PW (2009) Generation of human embryonic stem cell-derived mesoderm and cardiac cells using size-specified aggregates in an oxygen-controlled bioreactor. Biotechnol Bioeng 102(2):493–507

    Article  CAS  PubMed  Google Scholar 

  • Noseda M, Peterkin T, Simoes FC, Patient R, Schneider MD (2011) Cardiopoietic factors: extracellular signals for cardiac lineage commitment. Circ Res 108(1):129–152

    Article  CAS  PubMed  Google Scholar 

  • Novak A, Barad L, Zeevi-Levin N, Shick R, Shtrichman R, Lorber A, Itskovitz-Eldor J, Binah O (2012) Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to beta-adrenergic stimulation. J Cell Mol Med 16(3):468–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Novak A, Barad L, Lorber A, Gherghiceanu M, Reiter I, Eisen B, Eldor L, Itskovitz-Eldor J, Eldar M, Arad M, Binah O (2015) Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations. J Cell Mol Med 19(8):2006–2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ojala M, Prajapati C, Polonen RP, Rajala K, Pekkanen-Mattila M, Rasku J, Larsson K, Aalto-Setala K (2016) Mutation-specific phenotypes in hiPSC-derived cardiomyocytes carrying either myosin-binding protein C or alpha-tropomyosin mutation for hypertrophic cardiomyopathy. Stem Cells Int 2016:1684792

    Article  PubMed  CAS  Google Scholar 

  • Okawa S, del Sol A (2015) A computational strategy for predicting lineage specifiers in stem cell subpopulations. Stem Cell Res 15(2):427–434

    Article  CAS  PubMed  Google Scholar 

  • Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448(7151):313–317

    Article  CAS  PubMed  Google Scholar 

  • Ong SG, Huber BC, Lee WH, Kodo K, Ebert AD, Ma Y, Nguyen PK, Diecke S, Chen WY, Wu JC (2015) Microfluidic single-cell analysis of transplanted human induced pluripotent stem cell-derived cardiomyocytes after acute myocardial infarction. Circulation 132(8):762–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, Cowan CA, Chien KR, Melton DA (2008) Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol 26(3):313–315

    Article  CAS  PubMed  Google Scholar 

  • Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451(7175):141–146

    Article  CAS  PubMed  Google Scholar 

  • Penttinen K, Swan H, Vanninen S, Paavola J, Lahtinen AM, Kontula K, Aalto-Setala K (2015) Antiarrhythmic effects of dantrolene in patients with catecholaminergic polymorphic ventricular tachycardia and replication of the responses using iPSC models. PLoS One 10(5):e0125366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rana P, Anson B, Engle S, Will Y (2012) Characterization of human-induced pluripotent stem cell-derived cardiomyocytes: bioenergetics and utilization in safety screening. Toxicol Sci 130(1):117–131

    Article  CAS  PubMed  Google Scholar 

  • Rao J, Pfeiffer MJ, Frank S, Adachi K, Piccini I, Quaranta R, Arauzo-Bravo M, Schwarz J, Schade D, Leidel S, Scholer HR, Seebohm G, Greber B (2016) Stepwise clearance of repressive roadblocks drives cardiac induction in human ESCs. Cell Stem Cell 18(3):341–353

    Article  CAS  PubMed  Google Scholar 

  • Raval KK, Tao R, White BE, De Lange WJ, Koonce CH, Yu J, Kishnani PS, Thomson JA, Mosher DF, Ralphe JC, Kamp TJ (2015) Pompe disease results in a Golgi-based glycosylation deficit in human induced pluripotent stem cell-derived cardiomyocytes. J Biol Chem 290(5):3121–3136

    Article  CAS  PubMed  Google Scholar 

  • Ren Y, Lee MY, Schliffke S, Paavola J, Amos PJ, Ge X, Ye M, Zhu S, Senyei G, Lum L, Ehrlich BE, Qyang Y (2011) Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells. J Mol Cell Cardiol 51(3):280–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosen MR, Robinson RB, Brink PR, Cohen IS (2011) The road to biological pacing. Nat Rev Cardiol 8(11):656–666

    Article  PubMed  Google Scholar 

  • Saito Y, Nakamura K, Yoshida M, Sugiyama H, Ohe T, Kurokawa J, Furukawa T, Takano M, Nagase S, Morita H, Kusano KF, Ito H (2015) Enhancement of spontaneous activity by HCN4 overexpression in mouse embryonic stem cell-derived cardiomyocytes – a possible biological pacemaker. PLoS One 10(9):e0138193

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sato Y, Kobayashi H, Higuchi T, Shimada Y, Era T, Kimura S, Eto Y, Ida H, Ohashi T (2015) Disease modeling and lentiviral gene transfer in patient-specific induced pluripotent stem cells from late-onset Pompe disease patient. Mol Ther Methods Clin Dev 2:15023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schleich JM, Abdulla T, Summers R, Houyel L (2013) An overview of cardiac morphogenesis. Arch Cardiovasc Dis 106(11):612–623

    Article  PubMed  Google Scholar 

  • Shu J, Wu C, Wu Y, Li Z, Shao S, Zhao W, Tang X, Yang H, Shen L, Zuo X, Yang W, Shi Y, Chi X, Zhang H, Gao G, Shu Y, Yuan K, He W, Tang C, Zhao Y, Deng H (2013) Induction of pluripotency in mouse somatic cells with lineage specifiers. Cell 153(5):963–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siu CW, Lee YK, Ho JC, Lai WH, Chan YC, Ng KM, Wong LY, Au KW, Lau YM, Zhang J, Lay KW, Colman A, Tse HF (2012) Modeling of lamin a/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells. Aging (Albany NY) 4(11):803–822

    Article  CAS  Google Scholar 

  • Skrzynia C, Berg JS, Willis MS, Jensen BC (2015) Genetics and heart failure: a concise guide for the clinician. Curr Cardiol Rev 11(1):10–17

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336(6200):688–690

    Article  CAS  PubMed  Google Scholar 

  • Sun N, Yazawa M, Liu J, Han L, Sanchez-Freire V, Abilez OJ, Navarrete EG, Hu S, Wang L, Lee A, Pavlovic A, Lin S, Chen R, Hajjar RJ, Snyder MP, Dolmetsch RE, Butte MJ, Ashley EA, Longaker MT, Robbins RC, Wu JC (2012) Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med 4 (130):130ra147.

    Article  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  CAS  PubMed  Google Scholar 

  • Takei S, Ichikawa H, Johkura K, Mogi A, No H, Yoshie S, Tomotsune D, Sasaki K (2009) Bone morphogenetic protein-4 promotes induction of cardiomyocytes from human embryonic stem cells in serum-based embryoid body development. Am J Physiol Heart Circ Physiol 296(6):H1793–H1803

    Article  CAS  PubMed  Google Scholar 

  • Tanaka A, Yuasa S, Mearini G, Egashira T, Seki T, Kodaira M, Kusumoto D, Kuroda Y, Okata S, Suzuki T, Inohara T, Arimura T, Makino S, Kimura K, Kimura A, Furukawa T, Carrier L, Node K, Fukuda K (2014) Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes. J Am Heart Assoc 3(6):e001263

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y, Dawn B, Hunt G, Leri A, Kajstura J, Tiwari S, Shirk G, Anversa P, Bolli R (2010) Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 121(2):293–305

    Article  PubMed  PubMed Central  Google Scholar 

  • Terrenoire C, Wang K, Tung KW, Chung WK, Pass RH, Lu JT, Jean JC, Omari A, Sampson KJ, Kotton DN, Keller G, Kass RS (2013) Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol 141(1):61–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL, McKay RD (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448(7150):196–199

    Article  CAS  PubMed  Google Scholar 

  • Theis JL, Hrstka SC, Evans JM, O’Byrne MM, de Andrade M, O'Leary PW, Nelson TJ, Olson TM (2015) Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome. Hum Genet 134(9):1003–1011

    Article  CAS  PubMed  Google Scholar 

  • Theunissen TW, Powell BE, Wang H, Mitalipova M, Faddah DA, Reddy J, Fan ZP, Maetzel D, Ganz K, Shi L, Lungjangwa T, Imsoonthornruksa S, Stelzer Y, Rangarajan S, D'Alessio A, Zhang J, Gao Q, Dawlaty MM, Young RA, Gray NS, Jaenisch R (2014) Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 15(4):471–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147

    Article  CAS  PubMed  Google Scholar 

  • Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S (2011) Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell 145(6):875–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, Hashimoto H, Suzuki T, Yamashita H, Satoh Y, Egashira T, Seki T, Muraoka N, Yamakawa H, Ohgino Y, Tanaka T, Yoichi M, Yuasa S, Murata M, Suematsu M, Fukuda K (2013) Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12(1):127–137

    Article  CAS  PubMed  Google Scholar 

  • Tompkins JD, Jung M, Chen CY, Lin Z, Ye J, Godatha S, Lizhar E, Wu X, Hsu D, Couture LA, Riggs AD (2016) Mapping human pluripotent-to-cardiomyocyte differentiation: methylomes, transcriptomes, and exon DNA methylation “memories”. EBioMedicine 4:74–85

    Article  PubMed  PubMed Central  Google Scholar 

  • Tran TH, Wang X, Browne C, Zhang Y, Schinke M, Izumo S, Burcin M (2009) Wnt3a-induced mesoderm formation and cardiomyogenesis in human embryonic stem cells. Stem Cells 27(8):1869–1878

    Article  CAS  PubMed  Google Scholar 

  • Tse HF, Ho JC, Choi SW, Lee YK, Butler AW, Ng KM, Siu CW, Simpson MA, Lai WH, Chan YC, Au KW, Zhang J, Lay KW, Esteban MA, Nicholls JM, Colman A, Sham PC (2013) Patient-specific induced-pluripotent stem cells-derived cardiomyocytes recapitulate the pathogenic phenotypes of dilated cardiomyopathy due to a novel DES mutation identified by whole exome sequencing. Hum Mol Genet 22(7):1395–1403

    Article  CAS  PubMed  Google Scholar 

  • Uosaki H, Fukushima H, Takeuchi A, Matsuoka S, Nakatsuji N, Yamanaka S, Yamashita JK (2011) Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS One 6(8):e23657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vallier L, Alexander M, Pedersen RA (2005) Activin/nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 118(Pt 19):4495–4509

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Schulz TC, Sherrer ES, Dauphin DS, Shin S, Nelson AM, Ware CB, Zhan M, Song CZ, Chen X, Brimble SN, McLean A, Galeano MJ, Uhl EW, D'Amour KA, Chesnut JD, Rao MS, Blau CA, Robins AJ (2007) Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood 110(12):4111–4119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, Yuan H, Jiang D, Zhang D, Zangi L, Geva J, Roberts AE, Ma Q, Ding J, Chen J, Wang DZ, Li K, Wang J, Wanders RJ, Kulik W, Vaz FM, Laflamme MA, Murry CE, Chien KR, Kelley RI, Church GM, Parker KK, Pu WT (2014) Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med 20(6):616–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ware CB, Nelson AM, Mecham B, Hesson J, Zhou W, Jonlin EC, Jimenez-Caliani AJ, Deng X, Cavanaugh C, Cook S, Tesar PJ, Okada J, Margaretha L, Sperber H, Choi M, Blau CA, Treuting PM, Hawkins RD, Cirulli V, Ruohola-Baker H (2014) Derivation of naive human embryonic stem cells. Proc Natl Acad Sci U S A 111(12):4484–4489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen JY, Wei CY, Shah K, Wong J, Wang C, Chen HS (2015) Maturation-based model of arrhythmogenic right ventricular dysplasia using patient-specific induced pluripotent stem cells. Circ J 79(7):1402–1408

    Article  CAS  PubMed  Google Scholar 

  • Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448(7151):318–324

    Article  CAS  PubMed  Google Scholar 

  • Willems E, Spiering S, Davidovics H, Lanier M, Xia Z, Dawson M, Cashman J, Mercola M (2011) Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm. Circ Res 109(4):360–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willems E, Cabral-Teixeira J, Schade D, Cai W, Reeves P, Bushway PJ, Lanier M, Walsh C, Kirchhausen T, Izpisua Belmonte JC, Cashman J, Mercola M (2012) Small molecule-mediated TGF-beta type II receptor degradation promotes cardiomyogenesis in embryonic stem cells. Cell Stem Cell 11(2):242–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Lee J, Vincent LG, Wang Q, Gu M, Lan F, Churko JM, Sallam KI, Matsa E, Sharma A, Gold JD, Engler AJ, Xiang YK, Bers DM, Wu JC (2015) Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised beta-adrenergic signaling in an iPSC model of dilated cardiomyopathy. Cell Stem Cell 17(1):89–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong Q, Ye L, Zhang P, Lepley M, Tian J, Li J, Zhang L, Swingen C, Vaughan JT, Kaufman DS, Zhang J (2013) Functional consequences of human induced pluripotent stem cell therapy: myocardial ATP turnover rate in the in vivo swine heart with postinfarction remodeling. Circulation 127(9):997–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD, Carpenter MK (2001) Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol 19(10):971–974

    Article  CAS  PubMed  Google Scholar 

  • Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA (2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 20(12):1261–1264

    Article  CAS  PubMed  Google Scholar 

  • Xu C, Rosler E, Jiang J, Lebkowski JS, Gold JD, O'Sullivan C, Delavan-Boorsma K, Mok M, Bronstein A, Carpenter MK (2005a) Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium. Stem Cells 23(3):315–323

    Article  CAS  PubMed  Google Scholar 

  • Xu RH, Peck RM, Li DS, Feng X, Ludwig T, Thomson JA (2005b) Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods 2(3):185–190

    Article  CAS  PubMed  Google Scholar 

  • Xu XQ, Graichen R, Soo SY, Balakrishnan T, Rahmat SN, Sieh S, Tham SC, Freund C, Moore J, Mummery C, Colman A, Zweigerdt R, Davidson BP (2008) Chemically defined medium supporting cardiomyocyte differentiation of human embryonic stem cells. Differentiation 76(9):958–970

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM (2008) Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453(7194):524–528

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Pabon L, Murry CE (2014a) Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 114(3):511–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Rodriguez M, Pabon L, Fischer KA, Reinecke H, Regnier M, Sniadecki NJ, Ruohola-Baker H, Murry CE (2014b) Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J Mol Cell Cardiol 72:296–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao S, Chen S, Clark J, Hao E, Beattie GM, Hayek A, Ding S (2006) Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions. Proc Natl Acad Sci U S A 103(18):6907–6912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE (2011) Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471(7337):230–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye L, Chang YH, Xiong Q, Zhang P, Zhang L, Somasundaram P, Lepley M, Swingen C, Su L, Wendel JS, Guo J, Jang A, Rosenbush D, Greder L, Dutton JR, Zhang J, Kamp TJ, Kaufman DS, Ge Y, Zhang J (2014) Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell 15(6):750–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying QL, Nichols J, Chambers I, Smith A (2003) BMP induction of id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115(3):281–292

    Article  CAS  PubMed  Google Scholar 

  • Yu P, Pan G, Yu J, Thomson JA (2011) FGF2 sustains NANOG and switches the outcome of BMP4-induced human embryonic stem cell differentiation. Cell Stem Cell 8(3):326–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, Thomson JA, Kamp TJ (2009) Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 104(4):e30–e41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Jiang J, Han P, Yuan Q, Zhang J, Zhang X, Xu Y, Cao H, Meng Q, Chen L, Tian T, Wang X, Li P, Hescheler J, Ji G, Ma Y (2011) Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res 21(4):579–587

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Klos M, Wilson GF, Herman AM, Lian X, Raval KK, Barron MR, Hou L, Soerens AG, Yu J, Palecek SP, Lyons GE, Thomson JA, Herron TJ, Jalife J, Kamp TJ (2012) Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: the matrix sandwich method. Circ Res 111(9):1125–1136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XH, Haviland S, Wei H, Saric T, Fatima A, Hescheler J, Cleemann L, Morad M (2013) Ca2+ signaling in human induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) from normal and catecholaminergic polymorphic ventricular tachycardia (CPVT)-afflicted subjects. Cell Calcium 54(2):57–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Schulte JS, Heinick A, Piccini I, Rao J, Quaranta R, Zeuschner D, Malan D, Kim KP, Ropke A, Sasse P, Arauzo-Bravo M, Seebohm G, Scholer H, Fabritz L, Kirchhof P, Muller FU, Greber B (2015) Universal cardiac induction of human pluripotent stem cells in two and three-dimensional formats: implications for in vitro maturation. Stem Cells 33(5):1456–1469

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Cao N, Huang Y, Spencer CI, Fu JD, Yu C, Liu K, Nie B, Xu T, Li K, Xu S, Bruneau BG, Srivastava D, Ding S (2016) Expandable cardiovascular progenitor cells reprogrammed from fibroblasts. Cell Stem Cell 18(3):368–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu WZ, Xie Y, Moyes KW, Gold JD, Askari B, Laflamme MA (2010) Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells. Circ Res 107(6):776–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu R, Blazeski A, Poon E, Costa KD, Tung L, Boheler KR (2014) Physical developmental cues for the maturation of human pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther 5(5):117

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge funding support from the US National Institutes of Health R00 HL121177, the Dixon Translational Research Grant Young Investigator Award, and Innovation Development Progress (IDP) Research Innovation Challenge Grant (P.W.B.). We apologize to those investigators whose work was omitted here due to space limitations.

Compliance with Ethical Standards

Conflict of Interest

P.W.B. is on the scientific advisory board of Pluriomics B.V. and a shareholder in Stem Cell Theranostics.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul W. Burridge .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Schuldt, A.J.T., Romero-Tejeda, M., Burridge, P.W. (2017). Generation and Application of Human Pluripotent Stem Cell-Derived Cardiomyocytes. In: Ieda, M., Zimmermann, WH. (eds) Cardiac Regeneration. Cardiac and Vascular Biology, vol 4. Springer, Cham. https://doi.org/10.1007/978-3-319-56106-6_4

Download citation

Publish with us

Policies and ethics