Heart Failure Reviews

, Volume 18, Issue 6, pp 815–833 | Cite as

Myocardial regeneration of the failing heart

  • Alexander T. Akhmedov
  • José Marín-GarcíaEmail author


Human heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Currently, heart transplantation and implantation of mechanical devices represent the only available treatments for advanced HF. Two alternative strategies have emerged to treat patients with HF. One approach relies on transplantation of exogenous stem cells (SCs) of non-cardiac or cardiac origin to induce cardiac regeneration and improve ventricular function. Another complementary strategy relies on stimulation of the endogenous regenerative capacity of uninjured cardiac progenitor cells to rebuild cardiac muscle and restore ventricular function. Various SC types and delivery strategies have been examined in the experimental and clinical settings; however, neither the ideal cell type nor the cell delivery method for cardiac cell therapy has yet emerged. Although the use of bone marrow (BM)-derived cells, most frequently exploited in clinical trials, appears to be safe, the results are controversial. Two recent randomized trials have failed to document any beneficial effects of intracardiac delivery of autologous BM mononuclear cells on cardiac function of patients with HF. The remarkable discovery that various populations of cardiac progenitor cells (CPCs) are present in the adult human heart and that it possesses limited regeneration capacity has opened a new era in cardiac repair. Importantly, unlike BM-derived SCs, autologous CPCs from myocardial biopsies cultured and subsequently delivered by coronary injection to patients have given positive results. Although these data are promising, a better understanding of how to control proliferation and differentiation of CPCs, to enhance their recruitment and survival, is required before CPCs become clinically applicable therapeutics.


Heart failure Heart regeneration Stem cells Cardiac progenitor cells c-kit Isl1 Sca-1 


Conflict of interest

This manuscript entitled “Myocardial Regeneration of the Failing Heart” by A. T. Akhmedov and J. Marín-García which we are submitting for publication in Heart Failure Reviews has not been, nor will be published elsewhere, has been read and is submitted with the approval of all authors, all of which participated in the writing of the manuscript with no conflict of interest in its publication in Heart Failure Reviews.


  1. 1.
    Rosamond W et al (2007) Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115(5):e69–e171PubMedGoogle Scholar
  2. 2.
    Taylor DA, Zenovich AG (2008) Cardiovascular cell therapy and endogenous repair. Diabetes Obes Metab 10(Suppl 4):5–15PubMedGoogle Scholar
  3. 3.
    Roger VL et al (2011) Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123(4):e18–e209PubMedGoogle Scholar
  4. 4.
    Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900PubMedGoogle Scholar
  5. 5.
    Passier R, van Laake LW, Mummery CL (2008) Stem-cell-based therapy and lessons from the heart. Nature 453(7193):322–329PubMedGoogle Scholar
  6. 6.
    Laflamme MA, Murry CE (2011) Heart regeneration. Nature 473(7347):326–335PubMedGoogle Scholar
  7. 7.
    Choi WY, Poss KD (2012) Cardiac regeneration. Curr Top Dev Biol 100:319–344PubMedGoogle Scholar
  8. 8.
    Ptaszek LM et al (2012) Towards regenerative therapy for cardiac disease. Lancet 379(9819):933–942PubMedGoogle Scholar
  9. 9.
    Hwang H, Kloner RA (2010) Improving regenerating potential of the heart after myocardial infarction: factor-based approach. Life Sci 86(13–14):461–472PubMedGoogle Scholar
  10. 10.
    Ghadge SK et al (2011) SDF-1alpha as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol Ther 129(1):97–108PubMedGoogle Scholar
  11. 11.
    Limana F, Capogrossi MC, Germani A (2011) The epicardium in cardiac repair: from the stem cell view. Pharmacol Ther 129(1):82–96PubMedGoogle Scholar
  12. 12.
    Martinez EC, Kofidis T (2011) Adult stem cells for cardiac tissue engineering. J Mol Cell Cardiol 50(2):312–319PubMedGoogle Scholar
  13. 13.
    Zimmermann WH (2011) Embryonic and embryonic-like stem cells in heart muscle engineering. J Mol Cell Cardiol 50(2):320–326PubMedGoogle Scholar
  14. 14.
    Till JE, McCulloch EA, Siminovitch L (1964) A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proc Natl Acad Sci USA 51:29–36PubMedGoogle Scholar
  15. 15.
    Hagege AA et al (2003) Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 361(9356):491–492PubMedGoogle Scholar
  16. 16.
    Menasche P (2007) Skeletal myoblasts as a therapeutic agent. Prog Cardiovasc Dis 50(1):7–17PubMedGoogle Scholar
  17. 17.
    Olivares EL et al (2004) Bone marrow stromal cells improve cardiac performance in healed infarcted rat hearts. Am J Physiol Heart Circ Physiol 287(2):H464–H470PubMedGoogle Scholar
  18. 18.
    Xu M et al (2004) Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes. Circulation 110(17):2658–2665PubMedGoogle Scholar
  19. 19.
    Murry CE et al (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428(6983):664–668PubMedGoogle Scholar
  20. 20.
    Kao RL, Rizzo C, Magovern GJ (1989) Satellite cells for myocardial regeneration [abstract]. Physiologist 32:220Google Scholar
  21. 21.
    Taylor DA et al (1998) Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 4(8):929–933PubMedGoogle Scholar
  22. 22.
    Menasche P et al (2001) Myoblast transplantation for heart failure. Lancet 357(9252):279–280PubMedGoogle Scholar
  23. 23.
    Menasche P et al (2008) The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117(9):1189–1200PubMedGoogle Scholar
  24. 24.
    Siminiak T et al (2005) Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. Eur Heart J 26(12):1188–1195PubMedGoogle Scholar
  25. 25.
    Smits PC et al (2003) Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 42(12):2063–2069PubMedGoogle Scholar
  26. 26.
    Fernandes S et al (2006) Autologous myoblast transplantation after myocardial infarction increases the inducibility of ventricular arrhythmias. Cardiovasc Res 69(2):348–358PubMedGoogle Scholar
  27. 27.
    Yin AH et al (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90(12):5002–5012PubMedGoogle Scholar
  28. 28.
    Goodell MA et al (1997) Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3(12):1337–1345PubMedGoogle Scholar
  29. 29.
    Sato T, Laver JH, Ogawa M (1999) Reversible expression of CD34 by murine hematopoietic stem cells. Blood 94(8):2548–2554PubMedGoogle Scholar
  30. 30.
    Tomita S et al (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100(19 Suppl):II247–II256PubMedGoogle Scholar
  31. 31.
    Haider H, Ashraf M (2005) Bone marrow stem cell transplantation for cardiac repair. Am J Physiol Heart Circ Physiol 288(6):H2557–H2567PubMedGoogle Scholar
  32. 32.
    Pittenger MF et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147PubMedGoogle Scholar
  33. 33.
    Ryan JM et al (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2:8Google Scholar
  34. 34.
    Eisenberg LM, Burns L, Eisenberg CA (2003) Hematopoietic cells from bone marrow have the potential to differentiate into cardiomyocytes in vitro. Anat Rec A Discov Mol Cell Evol Biol 274(1):870–882PubMedGoogle Scholar
  35. 35.
    Alvarez-Dolado M et al (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425(6961):968–973PubMedGoogle Scholar
  36. 36.
    Nygren JM et al (2004) Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 10(5):494–501PubMedGoogle Scholar
  37. 37.
    Zhang N et al (2006) Blood-borne stem cells differentiate into vascular and cardiac lineages during normal development. Stem Cells Dev 15(1):17–28PubMedGoogle Scholar
  38. 38.
    Kawada H et al (2004) Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 104(12):3581–3587PubMedGoogle Scholar
  39. 39.
    Rota M et al (2007) Bone marrow cells adopt the cardiomyogenic fate in vivo. Proc Natl Acad Sci USA 104(45):17783–17788PubMedGoogle Scholar
  40. 40.
    Wollert KC et al (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364(9429):141–148PubMedGoogle Scholar
  41. 41.
    Janssens S et al (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367(9505):113–121PubMedGoogle Scholar
  42. 42.
    Lunde K et al (2006) Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 355(12):1199–1209PubMedGoogle Scholar
  43. 43.
    Assmus B et al (2010) Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail 3(1):89–96PubMedGoogle Scholar
  44. 44.
    Strauer BE, Yousef M, Schannwell CM (2010) The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 12(7):721–729PubMedGoogle Scholar
  45. 45.
    Zimmet H et al (2012) Short- and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials. Eur J Heart Fail 14(1):91–105PubMedGoogle Scholar
  46. 46.
    Perin EC et al (2012) Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 307(16):1717–1726Google Scholar
  47. 47.
    Korf-Klingebiel M et al (2008) Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction. Eur Heart J 29(23):2851–2858PubMedGoogle Scholar
  48. 48.
    Mirotsou M et al (2011) Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 50(2):280–289PubMedGoogle Scholar
  49. 49.
    Gluckman E et al (1989) Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 321(17):1174–1178PubMedGoogle Scholar
  50. 50.
    Kogler G et al (2004) A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 200(2):123–135PubMedGoogle Scholar
  51. 51.
    Gluckman E (2009) Ten years of cord blood transplantation: from bench to bedside. Br J Haematol 147(2):192–199PubMedGoogle Scholar
  52. 52.
    Henning RJ et al (2007) Human cord blood cells and myocardial infarction: effect of dose and route of administration on infarct size. Cell Transpl 16(9):907–917Google Scholar
  53. 53.
    Henning RJ et al (2010) Human umbilical cord blood mononuclear cells decrease fibrosis and increase cardiac function in cardiomyopathy. Regen Med 5(1):45–54PubMedGoogle Scholar
  54. 54.
    Kehat I et al (2001) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 108(3):407–414PubMedGoogle Scholar
  55. 55.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedGoogle Scholar
  56. 56.
    Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1(1):39–49PubMedGoogle Scholar
  57. 57.
    Thomson JA et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147PubMedGoogle Scholar
  58. 58.
    Passier R, Denning C, Mummery C (2006) Cardiomyocytes from human embryonic stem cells. Handb Exp Pharmacol 174:101–122PubMedGoogle Scholar
  59. 59.
    Orford KW, Scadden DT (2008) Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 9(2):115–128PubMedGoogle Scholar
  60. 60.
    Chen L, Daley GQ (2008) Molecular basis of pluripotency. Hum Mol Genet 17(R1):R23–R27PubMedGoogle Scholar
  61. 61.
    Murry CE, Keller G (2008) Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132(4):661–680PubMedGoogle Scholar
  62. 62.
    Mummery C et al (2003) Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107(21):2733–2740PubMedGoogle Scholar
  63. 63.
    Laflamme MA et al (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25(9):1015–1024PubMedGoogle Scholar
  64. 64.
    van Laake LW et al (2007) Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res 1(1):9–24PubMedGoogle Scholar
  65. 65.
    Laflamme MA, Murry CE (2005) Regenerating the heart. Nat Biotechnol 23(7):845–856PubMedGoogle Scholar
  66. 66.
    Liu YP et al (2004) Maintenance of pluripotency in human embryonic stem cells stably over-expressing enhanced green fluorescent protein. Stem Cells Dev 13(6):636–645PubMedGoogle Scholar
  67. 67.
    Nussbaum J et al (2007) Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J 21(7):1345–1357PubMedGoogle Scholar
  68. 68.
    Saric T, Frenzel LP, Hescheler J (2008) Immunological barriers to embryonic stem cell-derived therapies. Cells Tissues Organs 188(1–2):78–90PubMedGoogle Scholar
  69. 69.
    Trounson A et al (2011) Clinical trials for stem cell therapies. BMC Med 9:52PubMedGoogle Scholar
  70. 70.
    Jaenisch R, Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132(4):567–582PubMedGoogle Scholar
  71. 71.
    Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872PubMedGoogle Scholar
  72. 72.
    Shiba Y, Hauch KD, Laflamme MA (2009) Cardiac applications for human pluripotent stem cells. Curr Pharm Des 15(24):2791–2806PubMedGoogle Scholar
  73. 73.
    Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920PubMedGoogle Scholar
  74. 74.
    Dimos JT et al (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321(5893):1218–1221PubMedGoogle Scholar
  75. 75.
    Ebert AD et al (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457(7227):277–280PubMedGoogle Scholar
  76. 76.
    Hotta A et al (2009) Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nat Methods 6(5):370–376PubMedGoogle Scholar
  77. 77.
    Maehr R et al (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 106(37):15768–15773PubMedGoogle Scholar
  78. 78.
    Chambers I, Smith A (2004) Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23(43):7150–7160PubMedGoogle Scholar
  79. 79.
    Nakagawa M et al (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101–106PubMedGoogle Scholar
  80. 80.
    Wernig M et al (2008) c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2(1):10–12PubMedGoogle Scholar
  81. 81.
    Hanna J et al (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318(5858):1920–1923PubMedGoogle Scholar
  82. 82.
    Narazaki G et al (2008) Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation 118(5):498–506PubMedGoogle Scholar
  83. 83.
    Schenke-Layland K et al (2008) Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages. Stem Cells 26(6):1537–1546PubMedGoogle Scholar
  84. 84.
    Kuzmenkin A et al (2009) Functional characterization of cardiomyocytes derived from murine induced pluripotent stem cells in vitro. FASEB J 23(12):4168–4180PubMedGoogle Scholar
  85. 85.
    Yang L et al (2008) Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453(7194):524–528PubMedGoogle Scholar
  86. 86.
    Xu XQ et al (2008) Chemically defined medium supporting cardiomyocyte differentiation of human embryonic stem cells. Differentiation 76(9):958–970PubMedGoogle Scholar
  87. 87.
    Zhu WZ et al (2010) Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells. Circ Res 107(6):776–786PubMedGoogle Scholar
  88. 88.
    Paige SL et al (2010) Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLoS ONE 5(6):e11134PubMedGoogle Scholar
  89. 89.
    Noseda M et al (2011) Cardiopoietic factors: extracellular signals for cardiac lineage commitment. Circ Res 108(1):129–152PubMedGoogle Scholar
  90. 90.
    Shi Y et al (2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3(5):568–574PubMedGoogle Scholar
  91. 91.
    Ieda M et al (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142(3):375–386PubMedGoogle Scholar
  92. 92.
    Efe JA et al (2011) Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 13(3):215–222PubMedGoogle Scholar
  93. 93.
    Kim D et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4(6):472–476PubMedGoogle Scholar
  94. 94.
    Kaji K et al (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458(7239):771–775PubMedGoogle Scholar
  95. 95.
    Woltjen K et al (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458(7239):766–770PubMedGoogle Scholar
  96. 96.
    Yu J et al (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324(5928):797–801PubMedGoogle Scholar
  97. 97.
    Warren L et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5):618–630PubMedGoogle Scholar
  98. 98.
    Kelly RG, Brown NA, Buckingham ME (2001) The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 1(3):435–440PubMedGoogle Scholar
  99. 99.
    Mjaatvedt CH et al (2001) The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 238(1):97–109PubMedGoogle Scholar
  100. 100.
    Waldo KL et al (2001) Conotruncal myocardium arises from a secondary heart field. Development 128(16):3179–3188PubMedGoogle Scholar
  101. 101.
    Kelly RG (2012) The second heart field. Curr Top Dev Biol 100:33–65PubMedGoogle Scholar
  102. 102.
    Beltrami AP et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114(6):763–776PubMedGoogle Scholar
  103. 103.
    Linke A et al (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci USA 102(25):8966–8971PubMedGoogle Scholar
  104. 104.
    Urbanek K et al (2006) Stem cell niches in the adult mouse heart. Proc Natl Acad Sci USA 103(24):9226–9231PubMedGoogle Scholar
  105. 105.
    Bearzi C et al (2007) Human cardiac stem cells. Proc Natl Acad Sci USA 104(35):14068–14073PubMedGoogle Scholar
  106. 106.
    Bollini S, Smart N, Riley PR (2011) Resident cardiac progenitor cells: at the heart of regeneration. J Mol Cell Cardiol 50(2):296–303PubMedGoogle Scholar
  107. 107.
    Leri A, Kajstura J, Anversa P (2011) Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circ Res 109(8):941–961PubMedGoogle Scholar
  108. 108.
    Bernstein HS, Srivastava D (2012) Stem cell therapy for cardiac disease. Pediatr Res 71(4 Pt 2):491–499PubMedGoogle Scholar
  109. 109.
    Hosoda T et al (2009) Clonality of mouse and human cardiomyogenesis in vivo. Proc Natl Acad Sci USA 106(40):17169–17174PubMedGoogle Scholar
  110. 110.
    Goodell MA et al (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183(4):1797–1806PubMedGoogle Scholar
  111. 111.
    Martin CM et al (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 265(1):262–275PubMedGoogle Scholar
  112. 112.
    Pfister O et al (2008) Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. Circ Res 103(8):825–835PubMedGoogle Scholar
  113. 113.
    Pfister O et al (2010) Isolation of resident cardiac progenitor cells by Hoechst 33342 staining. Methods Mol Biol 660:53–63PubMedGoogle Scholar
  114. 114.
    Rasmussen TL et al (2011) Getting to the heart of myocardial stem cells and cell therapy. Circulation 123(16):1771–1779PubMedGoogle Scholar
  115. 115.
    Pfister O et al (2005) CD31− but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97(1):52–61PubMedGoogle Scholar
  116. 116.
    Wang X et al (2006) The role of the sca-1+/CD31− cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem Cells 24(7):1779–1788PubMedGoogle Scholar
  117. 117.
    Steinhauser ML, Lee RT (2011) Regeneration of the heart. EMBO Mol Med 3(12):701–712PubMedGoogle Scholar
  118. 118.
    Lyman SD, Jacobsen SE (1998) c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 91(4):1101–1134PubMedGoogle Scholar
  119. 119.
    Dawn B et al (2005) Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 102(10):3766–3771PubMedGoogle Scholar
  120. 120.
    Miyamoto S et al (2010) Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts. Stem Cells Dev 19(1):105–116PubMedGoogle Scholar
  121. 121.
    Tillmanns J et al (2008) Formation of large coronary arteries by cardiac progenitor cells. Proc Natl Acad Sci USA 105(5):1668–1673PubMedGoogle Scholar
  122. 122.
    Tang XL et al (2010) Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 121(2):293–305PubMedGoogle Scholar
  123. 123.
    Tallini YN et al (2009) c-kit expression identifies cardiovascular precursors in the neonatal heart. Proc Natl Acad Sci USA 106(6):1808–1813PubMedGoogle Scholar
  124. 124.
    Zaruba MM et al (2010) Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts. Circulation 121(18):1992–2000PubMedGoogle Scholar
  125. 125.
    Bolli R et al (2011) Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378(9806):1847–1857PubMedGoogle Scholar
  126. 126.
    Holmes C, Stanford WL (2007) Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells 25(6):1339–1347PubMedGoogle Scholar
  127. 127.
    Matsuura K et al (2004) Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. J Biol Chem 279(12):11384–11391PubMedGoogle Scholar
  128. 128.
    Matsuura K et al (2009) Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. J Clin Invest 119(8):2204–2217PubMedGoogle Scholar
  129. 129.
    Oh H et al (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100(21):12313–12318PubMedGoogle Scholar
  130. 130.
    Cai CL et al (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5(6):877–889PubMedGoogle Scholar
  131. 131.
    Laugwitz KL et al (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433(7026):647–653PubMedGoogle Scholar
  132. 132.
    Moretti A et al (2006) Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127(6):1151–1165PubMedGoogle Scholar
  133. 133.
    Moretti A et al (2010) Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors. FASEB J 24(3):700–711PubMedGoogle Scholar
  134. 134.
    Messina E et al (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95(9):911–921PubMedGoogle Scholar
  135. 135.
    Smith RR et al (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115(7):896–908PubMedGoogle Scholar
  136. 136.
    Chimenti I et al (2010) Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res 106(5):971–980PubMedGoogle Scholar
  137. 137.
    Bartosh TJ et al (2008) 3D-model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress. J Cell Biochem 105(2):612–623PubMedGoogle Scholar
  138. 138.
    Nelson TJ et al (2009) Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation 120(5):408–416PubMedGoogle Scholar
  139. 139.
    Johnston PV, et al (2009) Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120(12):1075–1083, 7 p following 1083Google Scholar
  140. 140.
    Lee ST et al (2011) 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 57(4):455–465PubMedGoogle Scholar
  141. 141.
    Andersen DC et al (2009) Murine “cardiospheres” are not a source of stem cells with cardiomyogenic potential. Stem Cells 27(7):1571–1581PubMedGoogle Scholar
  142. 142.
    Davis DR et al (2009) Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS ONE 4(9):e7195PubMedGoogle Scholar
  143. 143.
    Makkar RR et al (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379(9819):895–904PubMedGoogle Scholar
  144. 144.
    Siu CW, Tse HF (2012) Cardiac regeneration: messages from CADUCEUS. Lancet 379(9819):870–871PubMedGoogle Scholar
  145. 145.
    Ishii Y et al (2010) BMP signals promote proepicardial protrusion necessary for recruitment of coronary vessel and epicardial progenitors to the heart. Dev Cell 19(2):307–316PubMedGoogle Scholar
  146. 146.
    Merki E et al (2005) Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proc Natl Acad Sci USA 102(51):18455–18460PubMedGoogle Scholar
  147. 147.
    Limana F et al (2007) Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ Res 101(12):1255–1265PubMedGoogle Scholar
  148. 148.
    van Tuyn J et al (2007) Epicardial cells of human adults can undergo an epithelial-to-mesenchymal transition and obtain characteristics of smooth muscle cells in vitro. Stem Cells 25(2):271–278PubMedGoogle Scholar
  149. 149.
    Cai CL et al (2008) A myocardial lineage derives from Tbx18 epicardial cells. Nature 454(7200):104–108PubMedGoogle Scholar
  150. 150.
    Zhou B et al (2008) Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454(7200):109–113PubMedGoogle Scholar
  151. 151.
    Red-Horse K et al (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464(7288):549–553PubMedGoogle Scholar
  152. 152.
    Smart N et al (2007) Thymosin beta-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium. Ann N Y Acad Sci 1112:171–188PubMedGoogle Scholar
  153. 153.
    Bock-Marquette I et al (2009) Thymosin beta4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo. J Mol Cell Cardiol 46(5):728–738PubMedGoogle Scholar
  154. 154.
    Limana F et al (2010) Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid. J Mol Cell Cardiol 48(4):609–618PubMedGoogle Scholar
  155. 155.
    Smart N et al (2010) Thymosin beta4 facilitates epicardial neovascularization of the injured adult heart. Ann N Y Acad Sci 1194:97–104PubMedGoogle Scholar
  156. 156.
    Smart N et al (2011) De novo cardiomyocytes from within the activated adult heart after injury. Nature 474(7353):640–644PubMedGoogle Scholar
  157. 157.
    Zhou B et al (2011) Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest 121(5):1894–1904PubMedGoogle Scholar
  158. 158.
    Smart N et al (2007) Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445(7124):177–182PubMedGoogle Scholar
  159. 159.
    Ott HC et al (2007) The adult human heart as a source for stem cells: repair strategies with embryonic-like progenitor cells. Nat Clin Pract Cardiovasc Med 4(Suppl 1):S27–S39PubMedGoogle Scholar
  160. 160.
    Li RK, et al (1996) Cardiomyocyte transplantation improves heart function. Ann Thorac Surg 62(3):654–660; discussion 660–1Google Scholar
  161. 161.
    Scorsin M, et al (1997) Does transplantation of cardiomyocytes improve function of infarcted myocardium? Circulation 96(9 Suppl):II-188–II-193Google Scholar
  162. 162.
    Tsonis PA (1996) Limb Regeneration. Cambridge University Press, CambridgeGoogle Scholar
  163. 163.
    Rumyantsev PP (1973) Post-injury DNA synthesis, mitosis and ultrastructural reorganization of adult frog cardiac myocytes. An electron microscopic-autoradiographic study. Z Zellforsch Mikrosk Anat 139(3):431–450PubMedGoogle Scholar
  164. 164.
    Rumyantsev PP (1977) Interrelations of the proliferation and differentiation processes during cardiac myogenesis and regeneration. Int Rev Cytol 51:186–273PubMedGoogle Scholar
  165. 165.
    Oberpriller JO, Oberpriller JC (1974) Response of the adult newt ventricle to injury. J Exp Zool 187(2):249–253PubMedGoogle Scholar
  166. 166.
    Bader D, Oberpriller JO (1978) Repair and reorganization of minced cardiac muscle in the adult newt (Notophthalmus viridescens). J Morphol 155(3):349–357PubMedGoogle Scholar
  167. 167.
    Bader D, Oberpriller J (1979) Autoradiographic and electron microscopic studies of minced cardiac muscle regeneration in the adult newt, Notophthalmus viridescens. J Exp Zool 208(2):177–193PubMedGoogle Scholar
  168. 168.
    Oberpriller JO et al (1995) Stimulation of proliferative events in the adult amphibian cardiac myocyte. Ann N Y Acad Sci 752:30–46PubMedGoogle Scholar
  169. 169.
    Poss KD (2007) Getting to the heart of regeneration in zebrafish. Semin Cell Dev Biol 18(1):36–45PubMedGoogle Scholar
  170. 170.
    Poss KD (2010) Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat Rev Genet 11(10):710–722PubMedGoogle Scholar
  171. 171.
    Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in zebrafish. Science 298(5601):2188–2190PubMedGoogle Scholar
  172. 172.
    Lepilina A et al (2006) A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127(3):607–619PubMedGoogle Scholar
  173. 173.
    Kikuchi K et al (2010) Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464(7288):601–605PubMedGoogle Scholar
  174. 174.
    Jopling C et al (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464(7288):606–609PubMedGoogle Scholar
  175. 175.
    Chablais F et al (2011) The zebrafish heart regenerates after cryoinjury-induced myocardial infarction. BMC Dev Biol 11:21PubMedGoogle Scholar
  176. 176.
    Gonzalez-Rosa JM et al (2011) Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development 138(9):1663–1674PubMedGoogle Scholar
  177. 177.
    Schnabel K et al (2011) Regeneration of cryoinjury induced necrotic heart lesions in zebrafish is associated with epicardial activation and cardiomyocyte proliferation. PLoS ONE 6(4):e18503PubMedGoogle Scholar
  178. 178.
    Wang J et al (2011) The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion. Development 138(16):3421–3430PubMedGoogle Scholar
  179. 179.
    Li F et al (1996) Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol 28(8):1737–1746PubMedGoogle Scholar
  180. 180.
    Adler CP (1975) Relationship between deoxyribonucleic acid content and nucleoli in human heart muscle cells and estimation of cell number during cardiac growth and hyperfunction. Recent Adv Stud Cardiac Struct Metab 8:373–386PubMedGoogle Scholar
  181. 181.
    Bergmann O et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324(5923):98–102PubMedGoogle Scholar
  182. 182.
    Drenckhahn JD et al (2008) Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development. Dev Cell 15(4):521–533PubMedGoogle Scholar
  183. 183.
    Porrello ER et al (2011) Transient regenerative potential of the neonatal mouse heart. Science 331(6020):1078–1080PubMedGoogle Scholar
  184. 184.
    Bergmann O et al (2011) Identification of cardiomyocyte nuclei and assessment of ploidy for the analysis of cell turnover. Exp Cell Res 317(2):188–194PubMedGoogle Scholar
  185. 185.
    Kajstura J et al (2010) Cardiomyogenesis in the adult human heart. Circ Res 107(2):305–315PubMedGoogle Scholar
  186. 186.
    Dyer LA, Kirby ML (2009) The role of secondary heart field in cardiac development. Dev Biol 336(2):137–144PubMedGoogle Scholar
  187. 187.
    Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104(8):933–942PubMedGoogle Scholar
  188. 188.
    Vincent SD, Buckingham ME (2010) How to make a heart: the origin and regulation of cardiac progenitor cells. Curr Top Dev Biol 90:1–41PubMedGoogle Scholar
  189. 189.
    Bruneau BG (2002) Transcriptional regulation of vertebrate cardiac morphogenesis. Circ Res 90(5):509–519PubMedGoogle Scholar
  190. 190.
    Evans SM et al (2010) Myocardial lineage development. Circ Res 107(12):1428–1444PubMedGoogle Scholar
  191. 191.
    van Weerd JH et al (2011) Epigenetic factors and cardiac development. Cardiovasc Res 91(2):203–211PubMedGoogle Scholar
  192. 192.
    Behfar A et al (2002) Stem cell differentiation requires a paracrine pathway in the heart. FASEB J 16(12):1558–1566PubMedGoogle Scholar
  193. 193.
    Yuasa S et al (2005) Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol 23(5):607–611PubMedGoogle Scholar
  194. 194.
    Naito AT et al (2006) Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci USA 103(52):19812–19817PubMedGoogle Scholar
  195. 195.
    Kwon C et al (2007) Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proc Natl Acad Sci USA 104(26):10894–10899PubMedGoogle Scholar
  196. 196.
    Hao J et al (2008) Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells. PLoS ONE 3(8):e2904PubMedGoogle Scholar
  197. 197.
    Brennan J et al (2001) Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411(6840):965–969PubMedGoogle Scholar
  198. 198.
    Schultheiss TM, Burch JB, Lassar AB (1997) A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev 11(4):451–462PubMedGoogle Scholar
  199. 199.
    Foley AC, Mercola M (2005) Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes Dev 19(3):387–396PubMedGoogle Scholar
  200. 200.
    Ilagan R et al (2006) Fgf8 is required for anterior heart field development. Development 133(12):2435–2445PubMedGoogle Scholar
  201. 201.
    Park EJ et al (2006) Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development 133(12):2419–2433PubMedGoogle Scholar
  202. 202.
    Park EJ et al (2008) An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. Development 135(21):3599–3610PubMedGoogle Scholar
  203. 203.
    Urness LD et al (2011) Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development. Dev Biol 356(2):383–397PubMedGoogle Scholar
  204. 204.
    High FA, Epstein JA (2008) The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet 9(1):49–61PubMedGoogle Scholar
  205. 205.
    High FA et al (2009) Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. J Clin Invest 119(7):1986–1996PubMedGoogle Scholar
  206. 206.
    Kwon C et al (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11(8):951–957PubMedGoogle Scholar
  207. 207.
    Hutson MR et al (2010) Arterial pole progenitors interpret opposing FGF/BMP signals to proliferate or differentiate. Development 137(18):3001–3011PubMedGoogle Scholar
  208. 208.
    Tirosh-Finkel L et al (2010) BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors. Development 137(18):2989–3000PubMedGoogle Scholar
  209. 209.
    Thomas NA et al (2008) Hedgehog signaling plays a cell-autonomous role in maximizing cardiac developmental potential. Development 135(22):3789–3799PubMedGoogle Scholar
  210. 210.
    Dyer LA, Kirby ML (2009) Sonic hedgehog maintains proliferation in secondary heart field progenitors and is required for normal arterial pole formation. Dev Biol 330(2):305–317PubMedGoogle Scholar
  211. 211.
    Zhang XM, Ramalho-Santos M, McMahon AP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 105(6):781–792PubMedGoogle Scholar
  212. 212.
    Lavine KJ, Kovacs A, Ornitz DM (2008) Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice. J Clin Invest 118(7):2404–2414PubMedGoogle Scholar
  213. 213.
    Hoffmann AD et al (2009) sonic hedgehog is required in pulmonary endoderm for atrial septation. Development 136(10):1761–1770PubMedGoogle Scholar
  214. 214.
    Ryckebusch L et al (2008) Retinoic acid deficiency alters second heart field formation. Proc Natl Acad Sci USA 105(8):2913–2918PubMedGoogle Scholar
  215. 215.
    Sirbu IO, Zhao X, Duester G (2008) Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8 pathway. Dev Dyn 237(6):1627–1635PubMedGoogle Scholar
  216. 216.
    Li P, Pashmforoush M, Sucov HM (2010) Retinoic acid regulates differentiation of the secondary heart field and TGFbeta-mediated outflow tract septation. Dev Cell 18(3):480–485PubMedGoogle Scholar
  217. 217.
    Schleiffarth JR et al (2007) Wnt5a is required for cardiac outflow tract septation in mice. Pediatr Res 61(4):386–391PubMedGoogle Scholar
  218. 218.
    Zhou W et al (2007) Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nat Genet 39(10):1225–1234PubMedGoogle Scholar
  219. 219.
    Zhou Y et al (2011) Latent TGF-beta binding protein 3 identifies a second heart field in zebrafish. Nature 474(7353):645–648PubMedGoogle Scholar
  220. 220.
    Olivetti G et al (1991) Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68(6):1560–1568PubMedGoogle Scholar
  221. 221.
    Olivetti G et al (1997) Apoptosis in the failing human heart. N Engl J Med 336(16):1131–1141PubMedGoogle Scholar
  222. 222.
    Guerra S et al (1999) Myocyte death in the failing human heart is gender dependent. Circ Res 85(9):856–866PubMedGoogle Scholar
  223. 223.
    Murry CE, Reinecke H, Pabon LM (2006) Regeneration gaps: observations on stem cells and cardiac repair. J Am Coll Cardiol 47(9):1777–1785PubMedGoogle Scholar
  224. 224.
    Itzhaki-Alfia A et al (2009) Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells. Circulation 120(25):2559–2566PubMedGoogle Scholar
  225. 225.
    Lien CL et al (2006) Gene expression analysis of zebrafish heart regeneration. PLoS Biol 4(8):e260PubMedGoogle Scholar
  226. 226.
    Engel FB et al (2005) p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev 19(10):1175–1187PubMedGoogle Scholar
  227. 227.
    Engel FB et al (2006) FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci USA 103(42):15546–15551PubMedGoogle Scholar
  228. 228.
    Boni A et al (2008) Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci USA 105(40):15529–15534PubMedGoogle Scholar
  229. 229.
    Croquelois A et al (2008) Control of the adaptive response of the heart to stress via the Notch1 receptor pathway. J Exp Med 205(13):3173–3185PubMedGoogle Scholar
  230. 230.
    Collesi C et al (2008) Notch1 signaling stimulates proliferation of immature cardiomyocytes. J Cell Biol 183(1):117–128PubMedGoogle Scholar
  231. 231.
    Koyanagi M et al (2007) Notch signaling contributes to the expression of cardiac markers in human circulating progenitor cells. Circ Res 101(11):1139–1145PubMedGoogle Scholar
  232. 232.
    Rosenblatt-Velin N et al (2005) FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes. J Clin Invest 115(7):1724–1733PubMedGoogle Scholar
  233. 233.
    Urbanek K et al (2005) Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ Res 97(7):663–673PubMedGoogle Scholar
  234. 234.
    Rota M et al (2008) Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res 103(1):107–116PubMedGoogle Scholar
  235. 235.
    Aghila Rani KG, Kartha CC (2010) Effects of epidermal growth factor on proliferation and migration of cardiosphere-derived cells expanded from adult human heart. Growth Factors 28(3):157–165PubMedGoogle Scholar
  236. 236.
    Gonzalez A et al (2008) Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res 102(5):597–606PubMedGoogle Scholar
  237. 237.
    Gude NA et al (2008) Activation of Notch-mediated protective signaling in the myocardium. Circ Res 102(9):1025–1035PubMedGoogle Scholar
  238. 238.
    Sun Y (2010) Intracardiac renin-angiotensin system and myocardial repair/remodeling following infarction. J Mol Cell Cardiol 48(3):483–489PubMedGoogle Scholar
  239. 239.
    Segers VF, Lee RT (2010) Protein therapeutics for cardiac regeneration after myocardial infarction. J Cardiovasc Transl Res 3(5):469–477PubMedGoogle Scholar
  240. 240.
    Bocchi L et al (2011) Growth factor-induced mobilization of cardiac progenitor cells reduces the risk of arrhythmias, in a rat model of chronic myocardial infarction. PLoS ONE 6(3):e17750PubMedGoogle Scholar
  241. 241.
    Pesce M et al (2011) Endothelial and cardiac progenitors: boosting, conditioning and (re)programming for cardiovascular repair. Pharmacol Ther 129(1):50–61PubMedGoogle Scholar
  242. 242.
    Hoover-Plow J, Gong Y (2012) Challenges for heart disease stem cell therapy. Vasc Health Risk Manag 8:99–113PubMedGoogle Scholar
  243. 243.
    Bock-Marquette I et al (2004) Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432(7016):466–472PubMedGoogle Scholar
  244. 244.
    Srivastava D et al (2007) Thymosin beta4 is cardioprotective after myocardial infarction. Ann N Y Acad Sci 1112:161–170PubMedGoogle Scholar
  245. 245.
    Takahashi K et al (2008) Modulated inflammation by injection of high-mobility group box 1 recovers post-infarction chronically failing heart. Circulation 118(14 Suppl):S106–S114PubMedGoogle Scholar
  246. 246.
    Kohno T et al (2009) Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling. Cardiovasc Res 81(3):565–573PubMedGoogle Scholar
  247. 247.
    Palumbo R, Bianchi ME (2004) High mobility group box 1 protein, a cue for stem cell recruitment. Biochem Pharmacol 68(6):1165–1170PubMedGoogle Scholar
  248. 248.
    Palumbo R et al (2004) Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 164(3):441–449PubMedGoogle Scholar
  249. 249.
    Limana F et al (2005) Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res 97(8):e73–e83PubMedGoogle Scholar
  250. 250.
    Hofmann M et al (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111(17):2198–2202PubMedGoogle Scholar
  251. 251.
    Hou D et al (2005) Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112(9 Suppl):I150–I156PubMedGoogle Scholar
  252. 252.
    Perin EC, Lopez J (2006) Methods of stem cell delivery in cardiac diseases. Nat Clin Pract Cardiovasc Med 3(Suppl 1):S110–S113PubMedGoogle Scholar
  253. 253.
    Beeres SL et al (2008) Cell therapy for ischaemic heart disease. Heart 94(9):1214–1226PubMedGoogle Scholar
  254. 254.
    Martin-Rendon E et al (2008) Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 29(15):1807–1818PubMedGoogle Scholar
  255. 255.
    Freyman T et al (2006) A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J 27(9):1114–1122PubMedGoogle Scholar
  256. 256.
    Kurpisz M et al (2007) Bone marrow stem cell imaging after intracoronary administration. Int J Cardiol 121(2):194–195PubMedGoogle Scholar
  257. 257.
    Hare JM et al (2009) 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 54(24):2277–2286PubMedGoogle Scholar
  258. 258.
    Aicher A et al (2003) Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 107(16):2134–2139PubMedGoogle Scholar
  259. 259.
    Blocklet D et al (2006) Myocardial homing of nonmobilized peripheral-blood CD34+ cells after intracoronary injection. Stem Cells 24(2):333–336PubMedGoogle Scholar
  260. 260.
    Robey TE et al (2008) Systems approaches to preventing transplanted cell death in cardiac repair. J Mol Cell Cardiol 45(4):567–581PubMedGoogle Scholar
  261. 261.
    Muller-Ehmsen J et al (2002) Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J Mol Cell Cardiol 34(2):107–116PubMedGoogle Scholar
  262. 262.
    Zeng L et al (2007) Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling. Circulation 115(14):1866–1875PubMedGoogle Scholar
  263. 263.
    Hansson EM, Lindsay ME, Chien KR (2009) Regeneration next: toward heart stem cell therapeutics. Cell Stem Cell 5(4):364–377PubMedGoogle Scholar
  264. 264.
    Rangappa S, Makkar R, Forrester J (2010) Review article: current status of myocardial regeneration: new cell sources and new strategies. J Cardiovasc Pharmacol Ther 15(4):338–343PubMedGoogle Scholar
  265. 265.
    Malliaras K, Marban E (2011) Cardiac cell therapy: where we’ve been, where we are, and where we should be headed. Br Med Bull 98:161–185PubMedGoogle Scholar
  266. 266.
    Martens TP et al (2009) Percutaneous cell delivery into the heart using hydrogels polymerizing in situ. Cell Transpl 18(3):297–304Google Scholar
  267. 267.
    Hamdi H et al (2009) Cell delivery: intramyocardial injections or epicardial deposition? A head-to-head comparison. Ann Thorac Surg 87(4):1196–1203PubMedGoogle Scholar
  268. 268.
    Miyagawa S et al (2009) Combined autologous cellular cardiomyoplasty using skeletal myoblasts and bone marrow cells for human ischemic cardiomyopathy with left ventricular assist system implantation: report of a case. Surg Today 39(2):133–136PubMedGoogle Scholar
  269. 269.
    Miyagawa S et al (2011) Tissue-engineered cardiac constructs for cardiac repair. Ann Thorac Surg 91(1):320–329PubMedGoogle Scholar
  270. 270.
    Furuta A et al (2006) Pulsatile cardiac tissue grafts using a novel three-dimensional cell sheet manipulation technique functionally integrates with the host heart, in vivo. Circ Res 98(5):705–712PubMedGoogle Scholar
  271. 271.
    Domian IJ et al (2009) Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science 326(5951):426–429PubMedGoogle Scholar
  272. 272.
    Pasha Z et al (2008) Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res 77(1):134–142PubMedGoogle Scholar
  273. 273.
    Hu X et al (2008) Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 135(4):799–808PubMedGoogle Scholar
  274. 274.
    Haider H et al (2008) IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res 103(11):1300–1308PubMedGoogle Scholar
  275. 275.
    Traverse JH et al (2011) Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA 306(19):2110–2119PubMedGoogle Scholar
  276. 276.
    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10(1):32–42PubMedGoogle Scholar
  277. 277.
    Cordes KR, Srivastava D (2009) MicroRNA regulation of cardiovascular development. Circ Res 104(6):724–732PubMedGoogle Scholar
  278. 278.
    Jakob P, Landmesser U (2012) Role of microRNAs in stem/progenitor cells and cardiovascular repair. Cardiovasc Res 93(4):614–622PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.The Molecular Cardiology and Neuromuscular InstituteHighland ParkUSA

Personalised recommendations