Abstract
Congenital heart disease occurs in 1% of liveborn infants, making it the most common birth defect worldwide. Many of these children develop heart failure. In addition, both genetic and acquired forms of dilated cardiomyopathy are a significant source of heart failure in the pediatric population. Heart failure occurs when the myocardium is unable to meet the body’s metabolic demands. Unlike some organs, the heart has limited, if any, capacity for repair after injury. Heart transplantation remains the ultimate approach to treating heart failure, but this is costly and excludes patients who are poor candidates for transplantation given their comorbidities, or for whom a donor organ is unavailable. Stem cell therapy represents the first realistic strategy for reversing the effects of what has until now been considered terminal heart damage. We will discuss potential sources of cardiac-specific stem cells, including mesenchymal, resident cardiac, embryonic, and induced pluripotent stem cells. We will consider efforts to enhance cardiac stem cell engraftment and survival in damaged myocardium, the incorporation of cardiac stem cells into tissue patches, and techniques for creating bioartificial myocardial tissue as well as whole organs. Finally, we will review progress being made in assessing functional improvement in animals and humans after cellular transplant.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Lloyd-Jones D, Adams R, Carnethon M, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:480–6.
Hogg K, Swedberg K, McMurray J . Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol 2004;43:317–27.
Hoffman JI, Kaplan S . The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–900.
Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–9.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.
Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999;103:697–705.
Boyle AJ, McNiece IK, Hare JM . Mesenchymal stem cell therapy for cardiac repair. Methods Mol Biol 2010;660:65–84.
Alhadlaq A, Mao JJ . Mesenchymal stem cells: isolation and therapeutics. Stem Cells Dev 2004;13:436–48.
Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O . HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31:890–6.
Chen SL, Fang WW, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004;94:92–5.
Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277–86.
Rose RA, Keating A, Backx PH . Do mesenchymal stromal cells transdifferentiate into functional cardiomyocytes? Circ Res 2008;103:e120.
Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ . Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Physiol 1996;271(5 Pt 2):H2183–9.
Leri A, Barlucchi L, Limana F, et al. Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart. Proc Natl Acad Sci USA 2001;98:8626–31.
Oh H, Chi X, Bradfute SB, et al. Cardiac muscle plasticity in adult and embryo by heart-derived progenitor cells. Ann N Y Acad Sci 2004;1015:182–9.
Oh H, Wang SC, Prahash A, et al. Telomere attrition and Chk2 activation in human heart failure. Proc Natl Acad Sci USA 2003;100:5378–83.
Urbanek K, Quaini F, Tasca G, et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci USA 2003;100:10440–5.
Anversa P, Leri A, Kajstura J . Cardiac regeneration. J Am Coll Cardiol 2006;47:1769–76.
Hsieh PC, Segers VF, Davis ME, et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 2007;13:970–4.
Porrello ER, Mahmoud AI, Simpson E, et al. Transient regenerative potential of the neonatal mouse heart. Science 2011;331:1078–80.
Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009;324:98–102.
Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med 2002;346:5–15.
Oh H, Bradfute SB, Gallardo TD, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 2003;100:12313–8.
Dawn B, Stein AB, Urbanek K, et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 2005;102:3766–71.
Rota M, Padin-Iruegas ME, Misao Y, et al. Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res 2008;103:107–16.
Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells. Proc Natl Acad Sci USA 2007;104:14068–73.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183:1797–806.
Martin CM, Meeson AP, Robertson SM, et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 2004;265:262–75.
Pfister O, Oikonomopoulos A, Sereti KI, et al. Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. Circ Res 2008;103:825–35.
Pfister O, Mouquet F, Jain M, et al. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 2005;97:52–61.
Wang X, Hu Q, Nakamura Y, et al. The role of the sca-1+/CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem Cells 2006;24:1779–88.
Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 2004;95:911–21.
Ye J, Boyle A, Shih H, et al. Sca-1+ cardiosphere-derived cells are enriched for Isl1-expressing cardiac precursors and improve cardiac function after myocardial injury. PLoS One 2012;7:e30329.
Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 2007;115:896–908.
Bartosh TJ, Wang Z, Rosales AA, Dimitrijevich SD, Roque RS . 3D-model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress. J Cell Biochem 2008;105:612–23.
Takehara N, Tsutsumi Y, Tateishi K, et al. Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction. J Am Coll Cardiol 2008;52:1858–65.
Johnston PV, Sasano T, Mills K, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 2009;120:1075–83, 7 p following 1083.
Lee ST, White AJ, Matsushita S, et al. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol 2011;57:455–65.
Pouly J, Bruneval P, Mandet C, et al. Cardiac stem cells in the real world. J Thorac Cardiovasc Surg 2008;135:673–8.
Holmes C, Stanford WL . Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells 2007;25:1339–47.
Shenje LT, Field LJ, Pritchard CA, et al. Lineage tracing of cardiac explant derived cells. PLoS ONE 2008;3:e1929.
Li Z, Lee A, Huang M, et al. Imaging survival and function of transplanted cardiac resident stem cells. J Am Coll Cardiol 2009;53:1229–40.
Andersen DC, Andersen P, Schneider M, Jensen HB, Sheikh SP . Murine “cardiospheres” are not a source of stem cells with cardiomyogenic potential. Stem Cells 2009;27:1571–81.
Davis DR, Zhang Y, Smith RR, et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS ONE 2009;4:e7195.
Kehat I, Kenyagin-Karsenti D, Snir M, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 2001;108:407–14.
Wong SS, Bernstein HS . Cardiac regeneration using human embryonic stem cells: producing cells for future therapy. Regen Med 2010;5:763–75.
Xu XQ, Graichen R, Soo SY, et al. Chemically defined medium supporting cardiomyocyte differentiation of human embryonic stem cells. Differentiation 2008;76:958–70.
Xu C, Police S, Rao N, Carpenter MK . Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res 2002;91:501–8.
Graichen R, Xu X, Braam SR, et al. Enhanced cardiomyogenesis of human embryonic stem cells by a small molecular inhibitor of p38 MAPK. Differentiation 2008;76:357–70.
Gaur M, Ritner C, Sievers R, et al. Timed inhibition of p38MAPK directs accelerated differentiation of human embryonic stem cells into cardiomyocytes. Cytotherapy 2010;12:807–17.
Yang L, Soonpaa MH, Adler ED, et al. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 2008;453:524–8.
Zhao Y, Samal E, Srivastava D . Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 2005;436:214–20.
Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 2007;129:303–17.
Ivey KN, Muth A, Arnold J, et al. MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2008;2:219–29.
Wong SSY, Ritner C, Aurigui J, et al. miR-125b promotes cardiomyocyte differentiation of human embryonic stem cells. PLoS One 2012, in press.
Takeuchi JK, Bruneau BG . Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 2009;459:708–11.
Huber I, Itzhaki I, Caspi O, et al. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J 2007;21:2551–63.
Xu XQ, Zweigerdt R, Soo SY, et al. Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy 2008;10:376–89.
Kita-Matsuo H, Barcova M, Prigozhina N, et al. Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes. PLoS ONE 2009;4:e5046.
Ritner C, Wong SS, King FW, et al. An engineered cardiac reporter cell line identifies human embryonic stem cell-derived myocardial precursors. PLoS ONE 2011;6:e16004.
Anderson D, Self T, Mellor IR, Goh G, Hill SJ, Denning C . Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol Ther 2007; 15:2027–36.
King FW, Liszewski W, Ritner C, Bernstein HS . High-throughput tracking of pluripotent human embryonic stem cells with dual fluorescence resonance energy transfer molecular beacons. Stem Cells Dev 2011;20:475–84.
van Laake LW, Passier R, Monshouwer-Kloots J, et al. Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res 2007;1:9–24.
Leor J, Gerecht S, Cohen S, et al. Human embryonic stem cell transplantation to repair the infarcted myocardium. Heart 2007;93:1278–84.
Yeghiazarians Y, Gaur M, Zhang Y, et al. Myocardial improvement with human embryonic stem cell-derived cardiomyocytes enriched by p38MAPK inhibition. Cytotherapy 2012;14:223–31.
Drukker M, Katchman H, Katz G, et al. Human embryonic stem cells and their differentiated derivatives are less susceptible to immune rejection than adult cells. Stem Cells 2006;24:221–9.
Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–76.
Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861–72.
Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 2009;104:e30–41.
Zhao T, Zhang ZN, Rong Z, Xu Y . Immunogenicity of induced pluripotent stem cells. Nature 2011;474:212–5.
Nakajima F, Tokunaga K, Nakatsuji N . Human leukocyte antigen matching estimations in a hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy. Stem Cells 2007;25:983–5.
Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA . Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 2005;366:2019–25.
Yabut O, Bernstein HS . The promise of human embryonic stem cells in aging-associated diseases. Aging (Albany NY) 2011;3:494–508.
Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 2011;471:63–7.
Mayshar Y, Ben-David U, Lavon N, et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010;7:521–31.
Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009;4:381–4.
Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009;4:472–6.
Anokye-Danso F, Trivedi CM, Juhr D, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011;8:376–88.
Okita K, Matsumura Y, Sato Y, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods 2011;8:409–12.
Lister R, Pelizzola M, Kida YS, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 2011;471:68–73.
Ieda M, Fu JD, Delgado-Olguin P, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 2010;142:375–86.
Zimmermann WH, Melnychenko I, Wasmeier G, et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 2006;12:452–8.
Caspi O, Lesman A, Basevitch Y, et al. Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circ Res 2007;100:263–72.
Lesman A, Habib M, Caspi O, et al. Transplantation of a tissue-engineered human vascularized cardiac muscle. Tissue Eng Part A 2010;16:115–25.
Dvir T, Levy O, Shachar M, Granot Y, Cohen S . Activation of the ERK1/2 cascade via pulsatile interstitial fluid flow promotes cardiac tissue assembly. Tissue Eng 2007;13:2185–93.
Brown MA, Iyer RK, Radisic M . Pulsatile perfusion bioreactor for cardiac tissue engineering. Biotechnol Prog 2008;24:907–20.
Radisic M, Park H, Shing H, et al. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc Natl Acad Sci USA 2004;101:18129–34.
Tandon N, Cannizzaro C, Chao PH, et al. Electrical stimulation systems for cardiac tissue engineering. Nat Protoc 2009;4:155–73.
Dvir T, Kedem A, Ruvinov E, et al. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome. Proc Natl Acad Sci USA 2009;106:14990–5.
Ott HC, Matthiesen TS, Goh SK, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 2008;14:213–21.
Shimizu T, Yamato M, Isoi Y, et al. Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensional cell sheet manipulation technique and temperature-responsive cell culture surfaces. Circ Res 2002;90:e40.
Furuta A, Miyoshi S, Itabashi Y, et al. Pulsatile cardiac tissue grafts using a novel three-dimensional cell sheet manipulation technique functionally integrates with the host heart, in vivo. Circ Res 2006;98:705–12.
Amado LC, Schuleri KH, Saliaris AP, et al. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol 2006;48:2116–24.
Sebag IA, Handschumacher MD, Ichinose F, et al. Quantitative assessment of regional myocardial function in mice by tissue Doppler imaging: comparison with hemodynamics and sonomicrometry. Circulation 2005;111:2611–6.
Christoforou N, Oskouei BN, Esteso P, et al. Implantation of mouse embryonic stem cell-derived cardiac progenitor cells preserves function of infarcted murine hearts. PLoS ONE 2010;5:e11536.
Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 2002;73:1919–25; discussion 1926.
Abraham MR, Henrikson CA, Tung L, et al. Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation. Circ Res 2005;97:159–67.
Mummery C, Ward-van Oostwaard D, Doevendans P, et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 2003;107:2733–40.
Pekkanen-Mattila M, Chapman H, Kerkelä E, et al. Human embryonic stem cell-derived cardiomyocytes: demonstration of a portion of cardiac cells with fairly mature electrical phenotype. Exp Biol Med (Maywood) 2010;235:522–30.
Satin J, Kehat I, Caspi O, et al. Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J Physiol (Lond) 2004;559(Pt 2):479–96.
Verheule S, Wilson E, Banthia S, et al. Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation. Am J Physiol Heart Circ Physiol 2004;287:H634–44.
Gepstein L, Ding C, Rahmutula D, et al. In vivo assessment of the electrophysiological integration and arrhythmogenic risk of myocardial cell transplantation strategies. Stem Cells 2010;28:2151–61.
Kehat I, Khimovich L, Caspi O, et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 2004;22:1282–9.
Xue T, Cho HC, Akar FG, et al. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation 2005;111:11–20.
Acknowledgements
We apologize to colleagues whose work could not be cited due to space limitations. We thank the members of our laboratories for helpful discussion.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bernstein, H., Srivastava, D. Stem cell therapy for cardiac disease. Pediatr Res 71, 491–499 (2012). https://doi.org/10.1038/pr.2011.61
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2011.61
This article is cited by
-
Interplay of reactive oxygen species (ROS) and tissue engineering: a review on clinical aspects of ROS-responsive biomaterials
Journal of Materials Science (2021)
-
Therapeutic approach for global myocardial injury using bone marrow-derived mesenchymal stem cells by cardiac support device in rats
Biomedical Microdevices (2021)
-
Enhancing myocardial repair with CardioClusters
Nature Communications (2020)
-
Regenerative Therapy for Cardiomyopathies
Journal of Cardiovascular Translational Research (2018)
-
Mesenchymal stem cell in vitro labeling by hybrid fluorescent magnetic polymeric particles for application in cell tracking
Medical Molecular Morphology (2015)
