Current status of induced pluripotent stem cells in cardiac tissue regeneration and engineering

Regenerative Medicine Research - Tập 1 - Trang 1-10 - 2013
Zhiqiang Liu1, Jin Zhou1, Haibin Wang1, Mengge Zhao1,2, Changyong Wang1
1Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China
2Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, USA

Tóm tắt

Myocardial infarction (MI) is associated with damage to the myocardium which results in a great loss of functional cardiomyocytes. As one of the most terminally differentiated organs, the endogenous regenerative potentials of adult hearts are extremely limited and insufficient to compensate for the myocardial loss occurring after MI. Consequentially, exogenous regenerative strategies, especially cell replacement therapy, have emerged and attracted increasing more attention in the field of cardiac tissue regeneration. A renewable source of seeding cells is therefore one of the most important subject in the field. Induced pluripotent stem cells (iPSCs), embryonic stem cell (ESC)-like cells that are derived from somatic cells by reprogramming, represent a promising candidate due to their high potentials for self-renewal, proliferation, differentiation and more importantly, they provide an invaluable method of deriving patient-specific pluripotent stem cells. Therefore, iPSC-based cardiac tissue regeneration and engineering has been extensively investigated in recent years. This review will discuss the achievements and current status in this field, including development of iPSC derivation, in vitro strategies for cardiac generation from iPSCs, cardiac application of iPSCs, challenges confronted at present as well as perspective in the future.

Tài liệu tham khảo

Segers VF, Lee RT: Stem-cell therapy for cardiac disease. Nature 2008, 451: 937–942. 10.1038/nature06800 Zimmermann WH, Melnychenko I, Wasmeier G, Didie M, Naito H, Nixdorff U, Hess A, Budinsky L, Brune K, Michaelis B, Dhein S, Schwoerer A, Ehmke H, Eschenhagen T: Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 2006, 12: 452–458. 10.1038/nm1394 Patel J, Kobashigawa JA: Cardiac transplantation: the alternate list and expansion of the donor pool. Curr Opin Cardiol 2004, 19: 162–165. 10.1097/00001573-200403000-00017 Wang H, Zhou J, Liu Z, Wang C: Injectable cardiac tissue engineering for the treatment of myocardial infarction. J Cell Mol Med 2010, 14: 1044–1055. Hahn JY, Cho HJ, Kang HJ, Kim TS, Kim MH, Chung JH, Bae JW, Oh BH, Park YB, Kim HS: Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. J Am Coll Cardiol 2008, 51: 933–943. 10.1016/j.jacc.2007.11.040 Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ: Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 2004, 44: 654–660. 10.1016/j.jacc.2004.04.040 Gao LR, Wang ZG, Zhang NK, He S, Yao L, Ning HY, Kang XL, Fei YX, Zhu ZM, Yang Y: Transplantation of fetal cardiomyocyte regenerates infarcted myocardium in rats. Zhonghua Yi Xue Za Zhi 2003, 83: 1818–1822. Kofidis T, Lebl DR, Martinez EC, Hoyt G, Tanaka M, Robbins RC: Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury. Circulation 2005, 112: I173-I177. Lu WN, Lu SH, Wang HB, Li DX, Duan CM, Liu ZQ, Hao T, He WJ, Xu B, Fu Q, Song YC, Xie XH, Wang CY: Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A 2009, 15: 1437–1447. 10.1089/ten.tea.2008.0143 Passier R, van Laake LW, Mummery CL: Stem-cell-based therapy and lessons from the heart. Nature 2008, 453: 322–329. 10.1038/nature07040 Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren JM, Sasse P, Rubenchik O, Fries JW, Wenzel D, Geisen C, Xia Y, Lu Z, Duan Y, Kettenhofen R, Jovinge S, Bloch W, Bohlen H, Welz A, Hescheler J, Jacobsen SE, Fleischmann BK: Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 2006, 203: 2315–2327. 10.1084/jem.20061469 Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, Lee RT: Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 2003, 107: 1912–1916. 10.1161/01.CIR.0000064899.53876.A3 Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A, Yankelson L, Aronson D, Beyar R, Gepstein L: Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol 2007, 50: 1884–1893. 10.1016/j.jacc.2007.07.054 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: Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 2007, 25: 1015–1024. 10.1038/nbt1327 Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126: 663–676. 10.1016/j.cell.2006.07.024 Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier LS, Nguemo F, Menke S, Haustein M, Hescheler J, Hasenfuss G, Martin U: Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 2008, 118: 507–517. 10.1161/CIRCULATIONAHA.108.778795 Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, Thomson JA, Kamp TJ: Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 2009, 104: e30-e41. 10.1161/CIRCRESAHA.108.192237 Asgari S, Pournasr B, Salekdeh GH, Ghodsizadeh A, Ott M, Baharvand H: Induced pluripotent stem cells: a new era for hepatology. J Hepatol 2010, 53: 738–751. 10.1016/j.jhep.2010.05.009 Patel M, Yang S: Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Rev 2010, 6: 367–380. 10.1007/s12015-010-9123-8 Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R: In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007, 448: 318–324. 10.1038/nature05944 Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131: 861–872. 10.1016/j.cell.2007.11.019 Maherali N, Hochedlinger K: Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 2008, 3: 595–605. 10.1016/j.stem.2008.11.008 Zhao HX, Li Y, Jin HF, Xie L, Liu C, Jiang F, Luo YN, Yin GW, Wang J, Li LS, Yao YQ, Wang XH: Rapid and efficient reprogramming of human amnion-derived cells into pluripotency by three factors OCT4/SOX2/NANOG. Differentiation 2010, 80: 123–129. 10.1016/j.diff.2010.03.002 Giorgetti A, Montserrat N, Rodriguez-Piza I, Azqueta C, Veiga A, Izpisua Belmonte JC: Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2. Nat Protoc 2010, 5: 811–820. 10.1038/nprot.2010.16 Liu H, Zhu F, Yong J, Zhang P, Hou P, Li H, Jiang W, Cai J, Liu M, Cui K, Qu X, Xiang T, Lu D, Chi X, Gao G, Ji W, Ding M, Deng H: Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 2008, 3: 587–590. 10.1016/j.stem.2008.10.014 Ezashi T, Telugu BP, Alexenko AP, Sachdev S, Sinha S, Roberts RM: Derivation of induced pluripotent stem cells from pig somatic cells. Proc Natl Acad Sci USA 2009, 106: 10993–10998. 10.1073/pnas.0905284106 Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H, Ding S: Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 2009, 4: 16–19. 10.1016/j.stem.2008.11.014 Shimada H, Nakada A, Hashimoto Y, Shigeno K, Shionoya Y, Nakamura T: Generation of canine induced pluripotent stem cells by retroviral transduction and chemical inhibitors. Mol Reprod Dev 2010, 77: 2. Honda A, Hirose M, Hatori M, Matoba S, Miyoshi H, Inoue K, Ogura A: Generation of induced pluripotent stem cells in rabbits: potential experimental models for human regenerative medicine. J Biol Chem 2010, 285: 31362–31369. 10.1074/jbc.M110.150540 Li Y, Cang M, Lee AS, Zhang K, Liu D: Reprogramming of sheep fibroblasts into pluripotency under a drug-inducible expression of mouse-derived defined factors. PLoS ONE 2011, 6: e15947. 10.1371/journal.pone.0015947 Huang B, Li T, Alonso-Gonzalez L, Gorre R, Keatley S, Green A, Turner P, Kallingappa PK, Verma V, Oback B: A virus-free poly-promoter vector induces pluripotency in quiescent bovine cells under chemically defined conditions of dual kinase inhibition. PLoS ONE 2011, 6: e24501. 10.1371/journal.pone.0024501 Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S: Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008, 26: 101–106. 10.1038/nbt1374 Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K: Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 2008, 105: 2883–2888. 10.1073/pnas.0711983105 Stadtfeld M, Brennand K, Hochedlinger K: Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol 2008, 18: 890–894. 10.1016/j.cub.2008.05.010 Eminli S, Utikal J, Arnold K, Jaenisch R, Hochedlinger K: Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells 2008, 26: 2467–2474. 10.1634/stemcells.2008-0317 Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilic J, Pekarik V, Tiscornia G, Edel M, Boue S, Izpisua Belmonte JC: Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 2008, 26: 1276–1284. 10.1038/nbt.1503 Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K: Induced pluripotent stem cells generated without viral integration. Science 2008, 322: 945–949. 10.1126/science.1162494 Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S: Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008, 321: 699–702. 10.1126/science.1154884 Sun N, Panetta NJ, Gupta DM, Wilson KD, Lee A, Jia F, Hu S, Cherry AM, Robbins RC, Longaker MT, Wu JC: Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc Natl Acad Sci USA 2009, 106: 15720–15725. 10.1073/pnas.0908450106 Loh YH, Agarwal S, Park IH, Urbach A, Huo H, Heffner GC, Kim K, Miller JD, Ng K, Daley GQ: Generation of induced pluripotent stem cells from human blood. Blood 2009, 113: 5476–5479. 10.1182/blood-2009-02-204800 Okabe M, Otsu M, Ahn DH, Kobayashi T, Morita Y, Wakiyama Y, Onodera M, Eto K, Ema H, Nakauchi H: Definitive proof for direct reprogramming of hematopoietic cells to pluripotency. Blood 2009, 114: 1764–1767. 10.1182/blood-2009-02-203695 Utikal J, Maherali N, Kulalert W, Hochedlinger K: Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 2009, 122: 3502–3510. 10.1242/jcs.054783 Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodriguez-Piza I, Vassena R, Raya A, Boue S, Barrero MJ, Corbella BA, Torrabadella M, Veiga A, Izpisua Belmonte JC: Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 2009, 5: 353–357. Yan X, Qin H, Qu C, Tuan RS, Shi S, Huang GT: iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev 2010, 19: 469–480. 10.1089/scd.2009.0314 Seki T, Yuasa S, Oda M, Egashira T, Yae K, Kusumoto D, Nakata H, Tohyama S, Hashimoto H, Kodaira M, Okada Y, Seimiya H, Fusaki N, Hasegawa M, Fukuda K: Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 2010, 7: 11–14. 10.1016/j.stem.2010.06.003 Panopoulos AD, Ruiz S, Yi F, Herrerias A, Batchelder EM, Izpisua Belmonte JC: Rapid and highly efficient generation of induced pluripotent stem cells from human umbilical vein endothelial cells. PLoS ONE 2011, 6: e19743. 10.1371/journal.pone.0019743 Zhou T, Benda C, Duzinger S, Huang Y, Li X, Li Y, Guo X, Cao G, Chen S, Hao L, Chan YC, Ng KM, Ho JC, Wieser M, Wu J, Redl H, Tse HF, Grillari J, Grillari-Voglauer R, Pei D, Esteban MA: Generation of induced pluripotent stem cells from urine. J Am Soc Nephrol 2011, 22: 1221–1228. 10.1681/ASN.2011010106 Shi Y, Do JT, Desponts C, Hahm HS, Scholer HR, Ding S: A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2008, 2: 525–528. 10.1016/j.stem.2008.05.011 Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S: Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008, 322: 949–953. 10.1126/science.1164270 Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M: 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 2009, 85: 348–362. 10.2183/pjab.85.348 Abujarour R, Ding S: Induced pluripotent stem cells free of exogenous reprogramming factors. Genome Biol 2009, 10: 220. 10.1186/gb-2009-10-5-220 Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, Ding S: Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009, 4: 381–384. 10.1016/j.stem.2009.04.005 Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A: PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009, 458: 766–770. 10.1038/nature07863 Gonzalez F, Barragan Monasterio M, Tiscornia G, Montserrat Pulido N, Vassena R, Batlle Morera L, Rodriguez Piza I, Izpisua Belmonte JC: Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci USA 2009, 106: 8918–8922. 10.1073/pnas.0901471106 Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS: Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009, 4: 472–476. 10.1016/j.stem.2009.05.005 Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA: Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009, 324: 797–801. 10.1126/science.1172482 Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z, Panetta NJ, Chen ZY, Robbins RC, Kay MA, Longaker MT, Wu JC: A nonviral minicircle vector for deriving human iPS cells. Nat Methods 2010, 7: 197–199. 10.1038/nmeth.1426 Li Z, Yang CS, Nakashima K, Rana TM: Small RNA-mediated regulation of iPS cell generation. EMBO J 2011, 30: 823–834. 10.1038/emboj.2011.2 Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M: LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003, 302: 415–419. 10.1126/science.1088547 Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K: Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009, 458: 771–775. 10.1038/nature07864 Raya A, Rodriguez-Piza I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castella M, Rio P, Sleep E, Gonzalez F, Tiscornia G, Garreta E, Aasen T, Veiga A, Verma IM, Surralles J, Bueren J, Izpisua Belmonte JC: Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009, 460: 53–59. 10.1038/nature08129 Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R: Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007, 318: 1920–1923. 10.1126/science.1152092 Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R: Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA 2008, 105: 5856–5861. 10.1073/pnas.0801677105 Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A: Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation 2009, 120: 408–416. 10.1161/CIRCULATIONAHA.109.865154 Fujimoto Y, Abematsu M, Falk A, Tsujimura K, Sanosaka T, Juliandi B, Semi K, Namihira M, Komiya S, Smith A, Nakashima K: Treatment of a mouse model of spinal cord injury by transplantation of human iPS cell-derived long-term self-renewing neuroepithelial-like stem cells. Stem Cells 2012, 30: 1163–1173. 10.1002/stem.1083 Oki K, Tatarishvili J, Woods J, Koch P, Wattananit S, Mine Y, Monni E, Prietro DT, Ahlenius H, Ladewig J, Brustle O, Lindvall O, Kokaia Z: Human induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 2012, 30: 1120–1133. 10.1002/stem.1104 Chang HM, Liao YW, Chiang CH, Chen YJ, Lai YH, Chang YL, Chen HL, Jeng SY, Hsieh JH, Peng CH, Li HY, Chien Y, Chen SY, Chen LK, Huo TI: Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c-Myc. Int J Mol Sci 2012, 13: 3598–3617. 10.3390/ijms13033598 Malan D, Friedrichs S, Fleischmann BK, Sasse P: Cardiomyocytes obtained from induced pluripotent stem cells with long-QT syndrome 3 recapitulate typical disease-specific features in vitro. Circ Res 2011, 109: 841–847. 10.1161/CIRCRESAHA.111.243139 Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE: Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 2011, 471: 230–234. 10.1038/nature09855 Carvajal-Vergara X, Sevilla A, D’Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, Tartaglia M, Gelb BD, Lemischka IR: Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 2010, 465: 808–812. 10.1038/nature09005 Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ: Disease-specific induced pluripotent stem cells. Cell 2008, 134: 877–886. 10.1016/j.cell.2008.07.041 Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K: Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008, 321: 1218–1221. 10.1126/science.1158799 Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN: Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009, 457: 277–280. 10.1038/nature07677 Narazaki G, Uosaki H, Teranishi M, Okita K, Kim B, Matsuoka S, Yamanaka S, Yamashita JK: Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation 2008, 118: 498–506. 10.1161/CIRCULATIONAHA.108.769562 Uosaki H, Fukushima H, Takeuchi A, Matsuoka S, Nakatsuji N, Yamanaka S, Yamashita JK: Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS ONE 2011, 6: e23657. 10.1371/journal.pone.0023657 Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, Mahairaki V, Koliatsos VE, Tung L, Zambidis ET: A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS ONE 2011, 6: e18293. 10.1371/journal.pone.0018293 Kaichi S, Hasegawa K, Takaya T, Yokoo N, Mima T, Kawamura T, Morimoto T, Ono K, Baba S, Doi H, Yamanaka S, Nakahata T, Heike T: Cell line-dependent differentiation of induced pluripotent stem cells into cardiomyocytes in mice. Cardiovasc Res 2010, 88: 314–323. 10.1093/cvr/cvq189 Carpenter L, Carr C, Yang CT, Stuckey DJ, Clarke K, Watt SM: Efficient differentiation of human induced pluripotent stem cells generates cardiac cells that provide protection following myocardial infarction in the rat. Stem Cells Dev 2012, 21: 977–986. 10.1089/scd.2011.0075 Yokoo N, Baba S, Kaichi S, Niwa A, Mima T, Doi H, Yamanaka S, Nakahata T, Heike T: The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem Biophys Res Commun 2009, 387: 482–488. 10.1016/j.bbrc.2009.07.052 Zwi L, Caspi O, Arbel G, Huber I, Gepstein A, Park IH, Gepstein L: Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 2009, 120: 1513–1523. 10.1161/CIRCULATIONAHA.109.868885 Gai H, Leung EL, Costantino PD, Aguila JR, Nguyen DM, Fink LM, Ward DC, Ma Y: Generation and characterization of functional cardiomyocytes using induced pluripotent stem cells derived from human fibroblasts. Cell Biol Int 2009, 33: 1184–1193. 10.1016/j.cellbi.2009.08.008 Kuzmenkin A, Liang H, Xu G, Pfannkuche K, Eichhorn H, Fatima A, Luo H, Saric T, Wernig M, Jaenisch R, Hescheler J: Functional characterization of cardiomyocytes derived from murine induced pluripotent stem cells in vitro. FASEB J 2009, 23: 4168–4180. 10.1096/fj.08-128546 Moretti A, Bellin M, Jung CB, Thies TM, Takashima Y, Bernshausen A, Schiemann M, Fischer S, Moosmang S, Smith AG, Lam JT, Laugwitz KL: Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors. FASEB J 2010, 24: 700–711. 10.1096/fj.09-139477 Xi J, Khalil M, Shishechian N, Hannes T, Pfannkuche K, Liang H, Fatima A, Haustein M, Suhr F, Bloch W, Reppel M, Saric T, Wernig M, Janisch R, Brockmeier K, Hescheler J, Pillekamp F: Comparison of contractile behavior of native murine ventricular tissue and cardiomyocytes derived from embryonic or induced pluripotent stem cells. FASEB J 2010, 24: 2739–2751. 10.1096/fj.09-145177 Gupta MK, Illich DJ, Gaarz A, Matzkies M, Nguemo F, Pfannkuche K, Liang H, Classen S, Reppel M, Schultze JL, Hescheler J, Saric T: Global transcriptional profiles of beating clusters derived from human induced pluripotent stem cells and embryonic stem cells are highly similar. BMC Dev Biol 2010, 10: 98. 10.1186/1471-213X-10-98 Chan SS, Li HJ, Hsueh YC, Lee DS, Chen JH, Hwang SM, Chen CY, Shih E, Hsieh PC: Fibroblast growth factor-10 promotes cardiomyocyte differentiation from embryonic and induced pluripotent stem cells. PLoS ONE 2010, 5: e14414. 10.1371/journal.pone.0014414 Fujiwara M, Yan P, Otsuji TG, Narazaki G, Uosaki H, Fukushima H, Kuwahara K, Harada M, Matsuda H, Matsuoka S, Okita K, Takahashi K, Nakagawa M, Ikeda T, Sakata R, Mummery CL, Nakatsuji N, Yamanaka S, Nakao K, Yamashita JK: Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS ONE 2011, 6: e16734. 10.1371/journal.pone.0016734 Zwi-Dantsis L, Mizrahi I, Arbel G, Gepstein A, Gepstein L: Scalable production of cardiomyocytes derived from c-Myc free induced pluripotent stem cells. Tissue Eng Part A 2011, 17: 1027–1037. Quattrocelli M, Palazzolo G, Agnolin I, Martino S, Bouche M, Anastasia L, Sampaolesi M: Synthetic sulfonyl-hydrazone-1 positively regulates cardiomyogenic microRNA expression and cardiomyocyte differentiation of induced pluripotent stem cells. J Cell Biochem 2011, 112: 2006–2014. 10.1002/jcb.23118 So KH, Han YJ, Park HY, Kim JG, Sung DJ, Bae YM, Yang BC, Park SB, Chang SK, Kim EY, Park SP: Generation of functional cardiomyocytes from mouse induced pluripotent stem cells. Int J Cardiol 2011, 153: 277–285. 10.1016/j.ijcard.2010.08.052 Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF: Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. J Appl Physiol 2002, 92: 288–296. 10.1063/1.1481962 Cho SW, Gwak SJ, Kim IK, Cho MC, Hwang KK, Kwon JS, Choi CY, Yoo KJ, Kim BS: Granulocyte colony-stimulating factor treatment enhances the efficacy of cellular cardiomyoplasty with transplantation of embryonic stem cell-derived cardiomyocytes in infarcted myocardium. Biochem Biophys Res Commun 2006, 340: 573–582. 10.1016/j.bbrc.2005.12.044 Glass C, Singla DK: Overexpression of TIMP-1 in embryonic stem cells attenuates adverse cardiac remodeling following myocardial infarction. Cell Transplant 2012, 21: 1931–1944. 10.3727/096368911X627561 Caspi O, Lesman A, Basevitch Y, Gepstein A, Arbel G, Habib IH, Gepstein L, Levenberg S: Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circ Res 2007, 100: 263–272. 10.1161/01.RES.0000257776.05673.ff Li Z, Wilson KD, Smith B, Kraft DL, Jia F, Huang M, Xie X, Robbins RC, Gambhir SS, Weissman IL, Wu JC: Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. PLoS ONE 2009, 4: e8443. 10.1371/journal.pone.0008443 Rufaihah AJ, Haider HK, Heng BC, Ye L, Tan RS, Toh WS, Tian XF, Sim EK, Cao T: Therapeutic angiogenesis by transplantation of human embryonic stem cell-derived CD133+ endothelial progenitor cells for cardiac repair. Regen Med 2010, 5: 231–244. 10.2217/rme.09.83 Simpson DL, Boyd NL, Kaushal S, Stice SL, Dudley SC Jr: Use of human embryonic stem cell derived-mesenchymal cells for cardiac repair. Biotechnol Bioeng 2012, 109: 274–283. 10.1002/bit.23301 Ahmed RP, Ashraf M, Buccini S, Shujia J, Haider H: Cardiac tumorigenic potential of induced pluripotent stem cells in an immunocompetent host with myocardial infarction. Regen Med 2011, 6: 171–178. 10.2217/rme.10.103 Zhang Y, Wang D, Chen M, Yang B, Zhang F, Cao K: Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. PLoS ONE 2011, 6: e19012. 10.1371/journal.pone.0019012 Templin C, Zweigerdt R, Schwanke K, Olmer R, Ghadri JR, Emmert MY, Muller E, Kuest SM, Cohrs S, Schibli R, Kronen P, Hilbe M, Reinisch A, Strunk D, Haverich A, Hoerstrup S, Luscher TF, Kaufmann PA, Landmesser U, Martin U: Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression. Circulation 2012, 126: 430–439. 10.1161/CIRCULATIONAHA.111.087684 Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, Menke S, Glage S, Zweigerdt R, Haverich A, Martin U, Kutschka I: Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. Eur Heart J 2011, 32: 2634–2641. 10.1093/eurheartj/ehr166 Dai B, Huang W, Xu M, Millard RW, Gao MH, Hammond HK, Menick DR, Ashraf M, Wang Y: Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. J Am Coll Cardiol 2011, 58: 2118–2127. 10.1016/j.jacc.2011.06.062 Fu W, Wang SJ, Zhou GD, Liu W, Cao Y, Zhang WJ: Residual undifferentiated cells during differentiation of induced pluripotent stem cells in vitro and in vivo. Stem Cells Dev 2011, 21: 521–529. Zhao T, Zhang ZN, Rong Z, Xu Y: Immunogenicity of induced pluripotent stem cells. Nature 2011, 474: 212–215. 10.1038/nature10135 Song H, Yoon C, Kattman SJ, Dengler J, Masse S, Thavaratnam T, Gewarges M, Nanthakumar K, Rubart M, Keller GM, Radisic M, Zandstra PW: Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue. Proc Natl Acad Sci USA 2010, 107: 3329–3334. 10.1073/pnas.0905729106 Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L: Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009, 461: 402–406. 10.1038/nature08320 Lee G, Studer L: Modelling familial dysautonomia in human induced pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci 2011, 366: 2286–2296. 10.1098/rstb.2011.0026 Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S, Chen K, Li Y, Liu X, Xu J, Zhang S, Li F, He W, Labuda K, Song Y, Peterbauer A, Wolbank S, Redl H, Zhong M, Cai D, Zeng L, Pei D: Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 2010, 6: 71–79. 10.1016/j.stem.2009.12.001 Ieda M: Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Nihon Rinsho 2011,69(Suppl 7):524–527. Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F, Zanetta C, Faravelli I, Bresolin N, Comi GP: Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 2012, 318: 1528–1541. 10.1016/j.yexcr.2012.02.040