Skip to main content

Regenerative Mechanisms of the Adult Injured and Failing Heart

  • Chapter
  • First Online:
  • 2961 Accesses

Abstract

Many adult mammals’ organs—from the skin to skeletal muscle, bone marrow, liver, and intestine—have strong regenerative capacity. Even the heart in lower organisms has been shown to have an ability to regenerate, often observed in invertebrates such as salamander species. In recent years, some cardiac regenerative capacities have been observed in newts, salamanders, frogs, and neonatal rodents. This begs the question: What is the human heart’s potential for regeneration? Studies have firmly established that the adult mouse heart and human heart have the capacity for cardiomyocyte turnover and replacement. Increased cardiomyocyte content is expected to enhance vascular regeneration, given its role in promoting a microvascular endothelial network to provide oxygen and nutrients. Strategies to stimulate cardiac regeneration include reprogramming fibroblasts to cardiomyocytes, or converting them back to a stem cell state or to terminated lineages by forced expression. Signaling pathways and factors have been shown to modulate the capacity of cardiomyocyte proliferation. In addition, engineering strategies are being researched to either stimulate cardiac regeneration or replace lost myocardium. Examples include the use of “scaffolds” to deliver cells and the generation of sheets of cardiomyocytes for transplantation. With millions of people living with heart failure, the ability to promote new cardiomyocytes would be a life-changing therapy.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW, Woo YJ, American Heart Association Advocacy Coordinating Committee; Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council on Arteriosclerosis; Thrombosis and Vascular Biology; Council on Cardiopulmonary; Critical Care; Perioperative and Resuscitation; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease; Council on Cardiovascular Surgery and Anesthesia, and Interdisciplinary Council on Quality of Care and Outcomes Research. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933–44.

    Article  PubMed  Google Scholar 

  2. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117–71.

    Article  Google Scholar 

  3. Shepard D, VanderZanden A, Moran A, Naghavi M, Murray C, Roth G. Ischemic heart disease worldwide, 1990 to 2013: estimates from the global burden of disease study 2013. Circ Cardiovasc Qual Outcomes. 2015;8(4):455–6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol. 2010;72:19–44.

    Article  CAS  PubMed  Google Scholar 

  5. Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20(8):857–69.

    Article  CAS  PubMed  Google Scholar 

  6. van Berlo JH, Molkentin JD. An emerging consensus on cardiac regeneration. Nat Med. 2014;20(12):1386–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Tornini VA, Poss KD. Keeping at arm’s length during regeneration. Dev Cell. 2014;29(2):139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Singh BN, Koyano-Nakagawa N, Garry JP, Weaver CV. Heart of newt: a recipe for regeneration. J Cardiovasc Transl Res. 2010;3(4):397–409.

    Article  PubMed  Google Scholar 

  9. Oberpriller JO, Oberpriller JC. Response of the adult newt ventricle to injury. J Exp Zool. 1974;187(2):249–53.

    Article  CAS  PubMed  Google Scholar 

  10. Oberpriller J, Oberpriller JC. Mitosis in adult newt ventricle. J Cell Biol. 1971;49(2):560–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rumyantsev PP. Growth and hyperplasia of cardiac muscle cells. London: Harwood Academic Publishers; 1991.

    Google Scholar 

  12. Soonpaa MH, Field LJ. Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res. 1998;83(1):15–26.

    Article  CAS  PubMed  Google Scholar 

  13. Laube F, Heister M, Scholz C, Borchardt T, Braun T. Re-programming of newt cardiomyocytes is induced by tissue regeneration. J Cell Sci. 2006;119(Pt 22):4719–29.

    Article  CAS  PubMed  Google Scholar 

  14. Bettencourt-Dias M, Mittnacht S, Brockes JP. Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes. J Cell Sci. 2003;116(Pt 19):4001–9.

    Article  CAS  PubMed  Google Scholar 

  15. Piatkowski T, Mühlfeld C, Borchardt T, Braun T. Reconstitution of the myocardium in regenerating newt hearts is preceded by transient deposition of extracellular matrix components. Stem Cells Dev. 2013;22(13):1921–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Matz DG, Oberpriller JO, Oberpriller JC. Comparison of mitosis in binucleated and mononucleated newt cardiac myocytes. Anat Rec. 1998;251(2):245–55.

    Article  CAS  PubMed  Google Scholar 

  17. Oberpriller JO, Oberpriller JC, Arefyeva AM, Mitashov VI, Carlson BM. Nuclear characteristics of cardiac myocytes following the proliferative response to mincing of the myocardium in the adult newt. Notophthalmus viridescens. Cell Tissue Res. 1988;253(3):619–24.

    Article  CAS  PubMed  Google Scholar 

  18. Olivetti G, Cigola E, Maestri R, Corradi D, Lagrasta C, Gambert SR, Anversa P. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J Mol Cell Cardiol. 1996;28(7):1463–77.

    Article  CAS  PubMed  Google Scholar 

  19. Hayashi T, Yokotani N, Tane S, Matsumoto A, Myouga A, Okamoto M, Takeuchi T. Molecular genetic system for regenerative studies using newts. Dev Growth Differ. 2013;55(2):229–36.

    Article  PubMed  Google Scholar 

  20. Looso M, Preussner J, Sousounis K, Bruckskotten M, Michel CS, Lignelli E, Reinhardt R, Höffner S, Krüger M, Tsonis PA, Borchardt T, Braun T. A de novo assembly of the newt transcriptome combined with proteomic validation identifies new protein families expressed during tissue regeneration. Genome Biol. 2013;14(2):R16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Metscher BD, Ahlberg PE. Zebrafish in context: uses of a laboratory model in comparative studies. Dev Biol. 1999;210(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  22. Vacaru AM, Unlu G, Spitzner M, Mione M, Knapik EW, Sadler KC. In vivo cell biology in zebrafish – providing insights into vertebrate development and disease. J Cell Sci. 2014;127(Pt 3):485–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, Chow W, Kilian B, Quintais LT, Guerra-Assunção JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Threadgold G, Harden G, Ware D, Begum S, Mortimore B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring I, Berger A, Dooley CM, Ersan-Ürün Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, Oberländer M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nüsslein-Volhard C, Hubbard TJ, Roest Crollius H, Rogers J, Stemple DL. The zebrafish reference genome sequence and its relationship to the human genome. Nature. 2013;496(7446):498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science. 2002;298(5601):2188–90.

    Article  CAS  PubMed  Google Scholar 

  25. Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, Macrae CA, Stainier DY, Poss KD. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010;464(7288):601–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Leri A, Rota M, Pasqualini FS, Goichberg P, Anversa P. Origin of cardiomyocytes in the adult heart. Circ Res. 2015;116(1):150–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114(6):763–76.

    Article  CAS  PubMed  Google Scholar 

  28. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A. 2003;100(21):12313–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell. 2006;127(3):607–19.

    Article  CAS  PubMed  Google Scholar 

  30. Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, Rivera-Feliciano J, Jiang D, von Gise A, Ikeda S, Chien KR, Pu WT. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature. 2008;454(7200):109–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Smart N. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;474(7353):640–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou B, Honor LB, He H, Ma Q, Oh JH, Butterfield C, Lin RZ, Melero-Martin JM, Dolmatova E, Duffy HS, Gise AV, Zhou P, Hu YW, Wang G, Zhang B, Wang L, Hall JL, Moses MA, McGowan FX, Pu WT. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest. 2011;121(5):1894–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. de Pater E, Clijsters L, Marques SR, Lin YF, Garavito-Aguilar ZV, Yelon D, Bakkers J. Distinct phases of cardiomyocyte differentiation regulate growth of the zebrafish heart. Development. 2009;136(10):1633–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Kikuchi K, Gupta V, Wang J, Holdway JE, Wills AA, Fang Y, Poss KD. tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. Development. 2011;138(14):2895–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gupta V, Poss KD. Clonally dominant cardiomyocytes direct heart morphogenesis. Nature. 2012;484(7395):479–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xin M, Olson EN, Bassel-Duby R. Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol. 2013;14(8):529–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11(5):255–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. González-Rosa JM, Martín V, Peralta M, Torres M, Mercader N. Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development. 2011;138(9):1663–74.

    Article  PubMed  CAS  Google Scholar 

  39. Chablais F, Jazwinska A. The regenerative capacity of the zebrafish heart is dependent on TGFβ signaling. Development. 2012;139(11):1921–30.

    Article  CAS  PubMed  Google Scholar 

  40. Aurora AB, Olson EN. Immune modulation of stem cells and regeneration. Cell Stem Cell. 2014;15(1):14–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331(6020):1078–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Porrello ER, Mahmoud AI, Simpson E, Johnson BA, Grinsfelder D, Canseco D, Mammen PP, Rothermel BA, Olson EN, Sadek HA. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A. 2013;110(1):187–92.

    Article  CAS  PubMed  Google Scholar 

  43. Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, Sadek HA, Olson EN. Macrophages are required for neonatal heart regeneration. J Clin Invest. 2014;124(3):1382–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, André S, Crijns HJ, Gabius HJ, Maessen J, Pinto YM. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004;110(19):3121–8.

    Article  CAS  PubMed  Google Scholar 

  45. van Kimmenade RR, Januzzi Jr JL, Ellinor PT, Sharma UC, Bakker JA, Low AF, Martinez A, Crijns HJ, MacRae CA, Menheere PP, Pinto YM. Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol. 2006;48(6):1217–24.

    Article  PubMed  CAS  Google Scholar 

  46. Sizarov A, Ya J, de Boer BA, Lamers WH, Christoffels VM, Moorman AF. Formation of the building plan of the human heart: morphogenesis, growth, and differentiation. Circulation. 2011;123(10):1125–35.

    Article  PubMed  Google Scholar 

  47. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell. 2006;126(6):1037–48.

    Article  CAS  PubMed  Google Scholar 

  48. Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ, Duncan SA. Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol. 2008;317(2):614–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee RK, Stainier DY, Weinstein BM, Fishman MC. Cardiovascular development in the zebrafish. II. Endocardial progenitors are sequestered within the heart field. Development. 1994;120(12):3361–6.

    CAS  PubMed  Google Scholar 

  50. Zaffran S, Frasch M. Early signals in cardiac development. Circ Res. 2002;91(6):457–69.

    Article  CAS  PubMed  Google Scholar 

  51. Kathiriya IS, Nora EP, Bruneau BG. Investigating the transcriptional control of cardiovascular development. Circ Res. 2015;116(4):700–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bruneau BG. Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol. 2013;5(3):a008292.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Niessen K, Karsan A. Notch signaling in cardiac development. Circ Res. 2008;102(10):1169–81.

    Article  CAS  PubMed  Google Scholar 

  54. Duboc V, Lapraz F, Saudemont A, Bessodes N, Mekpoh F, Haillot E, Quirin M, Lepage T. Nodal and BMP2/4 pattern the mesoderm and endoderm during development of the sea urchin embryo. Development. 2010;137(2):223–35.

    Article  CAS  PubMed  Google Scholar 

  55. Palencia-Desai S, Kohli V, Kang J, Chi NC, Black BL, Sumanas S. Vascular endothelial and endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp/Etv2 function. Development. 2011;138(21):4721–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rasmussen TL, Kweon J, Diekmann MA, Belema-Bedada F, Song Q, Bowlin K, Shi X, Ferdous A, Li T, Kyba M, Metzger JM, Koyano-Nakagawa N, Garry DJ. ER71 directs mesodermal fate decisions during embryogenesis. Development. 2011;138(21):4801–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Saga Y, Miyagawa-Tomita S, Takagi A, Kitajima S, Miyazaki JI, Inoue T. MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development. 1999;126(15):3437–47.

    CAS  PubMed  Google Scholar 

  58. Bondue A, Lapouge G, Paulissen C, Semeraro C, Iacovino M, Kyba M, Blanpain C. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell. 2008;3(1):69–84.

    Article  CAS  PubMed  Google Scholar 

  59. Kruithof BP, van Wijk B, Somi S, Kruithof-de Julio M, Pérez Pomares JM, Weesie F, Wessels A, Moorman AF, van den Hoff MJ. BMP and FGF regulate the differentiation of multipotential pericardial mesoderm into the myocardial or epicardial lineage. Dev Biol. 2006;295(2):507–22.

    Article  CAS  PubMed  Google Scholar 

  60. von Gise A, Pu WT. Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ Res. 2012;110(12):1628–45.

    Article  CAS  Google Scholar 

  61. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cardiac neural crest. Development. 2000;127(8):1607–16.

    CAS  PubMed  Google Scholar 

  62. Brown CB, Feiner L, Lu MM, Li J, Ma X, Webber AL, Jia L, Raper JA, Epstein JA. PlexinA2 and semaphorin signaling during cardiac neural crest development. Development. 2001;128(16):3071–80.

    CAS  PubMed  Google Scholar 

  63. Epstein JA, Aghajanian H, Singh MK. Semaphorin signaling in cardiovascular development. Cell Metab. 2015;21(2):163–73.

    Article  CAS  PubMed  Google Scholar 

  64. Kimura K, Ieda M, Fukuda K. Development, maturation, and transdifferentiation of cardiac sympathetic nerves. Circ Res. 2012;110(2):325–36.

    Article  CAS  PubMed  Google Scholar 

  65. Sato M, Yost HJ. Cardiac neural crest contributes to cardiomyogenesis in zebrafish. Dev Biol. 2003;257(1):127–39.

    Article  CAS  PubMed  Google Scholar 

  66. Danielian PS, Muccino D, Rowitch DH, Michael SK, McMahon AP. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol. 1998;8(24):1323–6.

    Article  CAS  PubMed  Google Scholar 

  67. Tomita Y, Matsumura K, Wakamatsu Y, Matsuzaki Y, Shibuya I, Kawaguchi H, Ieda M, Kanakubo S, Shimazaki T, Ogawa S, Osumi N, Okano H, Fukuda K. Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart. J Cell Biol. 2005;170(7):1135–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mikkola HK, Orkin SH. The journey of developing hematopoietic stem cells. Development. 2006;133(19):3733–44.

    Article  CAS  PubMed  Google Scholar 

  69. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.

    Article  CAS  PubMed  Google Scholar 

  70. Gros J, Manceau M, Thomé V, Marcelle C. A common somitic origin for embryonic muscle progenitors and satellite cells. Nature. 2005;435(7044):954–8.

    Article  CAS  PubMed  Google Scholar 

  71. Wu SM, Chien KR, Mummery C. Origins and fates of cardiovascular progenitor cells. Cell. 2008;132(4):537–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 1995;9(13):1654–66.

    Article  CAS  PubMed  Google Scholar 

  73. Prall OW, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, Bajolle F, Biben C, McBride JJ, Robertson BR, Chaulet H, Stennard FA, Wise N, Schaft D, Wolstein O, Furtado MB, Shiratori H, Chien KR, Hamada H, Black BL, Saga Y, Robertson EJ, Buckingham ME, Harvey RP. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell. 2007;128(5):947–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell. 2006;127(6):1137–50.

    Article  CAS  PubMed  Google Scholar 

  75. Chen WP, Wu SM. Small molecule regulators of postnatal Nkx2.5 cardiomyoblast proliferation and differentiation. J Cell Mol Med. 2012;16(5):961–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen WP, Liu YH, Ho YJ, Wu SM. Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res. 2015;105(1):44–54.

    Article  CAS  PubMed  Google Scholar 

  77. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003;5(6):877–89.

    Article  CAS  PubMed  Google Scholar 

  78. Engleka KA, Manderfield LJ, Brust RD, Li L, Cohen A, Dymecki SM, Epstein JA. Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res. 2012;110(7):922–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Weinberger F, Mehrkens D, Friedrich FW, Stubbendorff M, Hua X, Müller JC, Schrepfer S, Evans SM, Carrier L, Eschenhagen T. Localization of Islet-1-positive cells in the healthy and infarcted adult murine heart. Circ Res. 2012;110(10):1303–10.

    Article  CAS  PubMed  Google Scholar 

  80. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature. 2005;433(7026):647–53.

    Article  CAS  PubMed  Google Scholar 

  81. Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L, Jiang X, Lin L, Granger A, Moretti A, Caron L, Wu X, Clarke J, Taketo MM, Laugwitz KL, Moon RT, Gruber P, Evans SM, Ding S, Chien KR. The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway. Cell Stem Cell. 2007;1(2):165–79.

    Article  CAS  PubMed  Google Scholar 

  82. Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, Raval KK, Zhang J, Kamp TJ, Palecek SP. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A. 2012;109(27):E1848–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lian X, Zhang J, Azarin SM, Zhu K, Hazeltine LB, Bao X, Hsiao C, Kamp TJ, Palecek SP. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat Protoc. 2013;8(1):162–75.

    Article  CAS  PubMed  Google Scholar 

  84. Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature. 2008;453(7194):524–8.

    Article  CAS  PubMed  Google Scholar 

  85. Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, Chen Y, Qyang Y, Bu L, Sasaki M, Martin-Puig S, Sun Y, Evans SM, Laugwitz KL, Chien KR. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell. 2006;127(6):1151–65.

    Article  CAS  PubMed  Google Scholar 

  86. Cai CL, Martin JC, Sun Y, Cui L, Wang L, Ouyang K, Yang L, Bu L, Liang X, Zhang X, Stallcup WB, Denton CP, McCulloch A, Chen J, Evans SM. A myocardial lineage derives from Tbx18 epicardial cells. Nature. 2008;454(7200):104–8.

    Article  CAS  PubMed  Google Scholar 

  87. Christoffels VM, Grieskamp T, Norden J, Mommersteeg MT, Rudat C, Kispert A. Tbx18 and the fate of epicardial progenitors. Nature. 2009;458(7240):E8–9. discussion E9-10.

    Article  CAS  PubMed  Google Scholar 

  88. Pierpont ME, Basson CT, Benson Jr DW, Gelb BD, Giglia TM, Goldmuntz E, McGee G, Sable CA, Srivastava D, Webb CL, American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115(23):3015–38.

    Article  PubMed  Google Scholar 

  89. Fahed AC, Gelb BD, Seidman JG, Seidman CE. Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112(4):707–20.

    Article  CAS  PubMed  Google Scholar 

  90. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270–4.

    Article  CAS  PubMed  Google Scholar 

  91. Nemer G, Fadlalah F, Usta J, Nemer M, Dbaibo G, Obeid M, Bitar F. A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot. Hum Mutat. 2006;27(3):293–4.

    Article  PubMed  Google Scholar 

  92. Molkentin JD, Lin Q, Duncan SA, Olson EN. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 1997;11(8):1061–72.

    Article  CAS  PubMed  Google Scholar 

  93. Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 1997;11(8):1048–60.

    Article  CAS  PubMed  Google Scholar 

  94. Horb ME, Thomsen GH. Tbx5 is essential for heart development. Development. 1999;126(8):1739–51.

    CAS  PubMed  Google Scholar 

  95. Bruneau BG, Nemer G, Schmitt JP, Charron F, Robitaille L, Caron S, Conner DA, Gessler M, Nemer M, Seidman CE, Seidman JG. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell. 2001;106(6):709–21.

    Article  CAS  PubMed  Google Scholar 

  96. Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15(1):30–5.

    Article  CAS  PubMed  Google Scholar 

  97. O’Meara CC, Wamstad JA, Gladstone RA, Fomovsky GM, Butty VL, Shrikumar A, Gannon JB, Boyer LA, Lee RT. Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration. Circ Res. 2015;116(5):804–15.

    Article  PubMed  CAS  Google Scholar 

  98. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142(3):375–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao B, Tumaneng K, Guan KL. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011;13(8):877–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24(9):862–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332(6028):458–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011;4(196):ra70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Lin Z, von Gise A, Zhou P, Gu F, Ma Q, Jiang J, Yau AL, Buck JN, Gouin KA, van Gorp PR, Zhou B, Chen J, Seidman JG, Wang DZ, Pu WT. Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ Res. 2014;115(3):354–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. von Gise A, Lin Z, Schlegelmilch K, Honor LB, Pan GM, Buck JN, Ma Q, Ishiwata T, Zhou B, Camargo FD, Pu WT. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A. 2012;109(7):2394–9.

    Article  Google Scholar 

  105. Li J, Gao E, Vite A, Yi R, Gomez L, Goossens S, van Roy F, Radice GL. Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity. Circ Res. 2015;116(1):70–9.

    Article  CAS  PubMed  Google Scholar 

  106. Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, Snitow M, Morley M, Li D, Petrenko N, Zhou S, Lu M, Gao E, Koch WJ, Stewart KM, Morrisey EE. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci Transl Med. 2015;7(279):279ra38.

    Article  PubMed  CAS  Google Scholar 

  107. Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL, Szewczykowska M, Jackowska T, Dos Remedios C, Malm T, Andrä M, Jashari R, Nyengaard JR, Possnert G, Jovinge S, Druid H, Frisén J. Dynamics of cell generation and turnover in the human heart. Cell. 2015;161(7):1566–75.

    Article  CAS  PubMed  Google Scholar 

  108. Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007;13(8):970–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013;493(7432):433–6.

    Article  CAS  PubMed  Google Scholar 

  110. Herget GW, Neuburger M, Plagwitz R, Adler CP. DNA content, ploidy level and number of nuclei in the human heart after myocardial infarction. Cardiovasc Res. 1997;36(1):45–51.

    Article  CAS  PubMed  Google Scholar 

  111. Adler CP, Friedburg H, Herget GW, Neuburger M, Schwalb H. Variability of cardiomyocyte DNA content, ploidy level and nuclear number in mammalian hearts. Virchows Arch. 1996;429(2-3):159–64.

    CAS  PubMed  Google Scholar 

  112. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Anderson EC, Libby WF, Weinhouse S, Reid AF, Kirshenbaum AD, Grosse AV. Radiocarbon from cosmic radiation. Science. 1947;105(2735):576–7.

    Article  CAS  PubMed  Google Scholar 

  114. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisén J. Retrospective birth dating of cells in humans. Cell. 2005;122(1):133–43.

    Article  CAS  PubMed  Google Scholar 

  115. Bergmann O, Zdunek S, Alkass K, Druid H, Bernard S, Frisén J. Identification of cardiomyocyte nuclei and assessment of ploidy for the analysis of cell turnover. Exp Cell Res. 2011;317(2):188–94.

    Article  CAS  PubMed  Google Scholar 

  116. Murry CE, Lee RT. Development biology. Turnover after the fallout. Science. 2009;324(5923):47–8.

    Article  CAS  PubMed  Google Scholar 

  117. Steinhauser ML, Bailey AP, Senyo SE, Guillermier C, Perlstein TS, Gould AP, Lee RT, Lechene CP. Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. Nature. 2012;481(7382):516–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ang KL, Shenje LT, Reuter S, Soonpaa MH, Rubart M, Field LJ, Galiñanes M. Limitations of conventional approaches to identify myocyte nuclei in histologic sections of the heart. Am J Physiol Cell Physiol. 2010;298(6):C1603–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol. 1997;272(1 Pt 2):H220–6.

    CAS  PubMed  Google Scholar 

  120. 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.

    CAS  PubMed  Google Scholar 

  121. Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. 2001;344(23):1750–7.

    Article  CAS  PubMed  Google Scholar 

  122. Loffredo FS, Steinhauser ML, Gannon J, Lee RT. Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell. 2011;8(4):389–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE, Dulce R, Pattany PM, Valdes D, Revilla C, Heldman AW, McNiece I, Hare JM. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107(7):913–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ali SR, Hippenmeyer S, Saadat LV, Luo L, Weissman IL, Ardehali R. Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc Natl Acad Sci U S A. 2014;111(24):8850–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Martin CM, Meeson AP, Robertson SM, Hawke TJ, Richardson JA, Bates S, Goetsch SC, Gallardo TD, Garry DJ. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol. 2004;265(1):262–75.

    Article  CAS  PubMed  Google Scholar 

  126. Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A. The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature. 1988;335(6185):88–9.

    Article  CAS  PubMed  Google Scholar 

  127. Ikuta K, Weissman IL. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci U S A. 1992;89(4):1502–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Briddell RA. Further phenotypic characterization and isolation of human hematopoietic progenitor cells using a monoclonal antibody to the c-kit receptor. Blood. 1992;79(12):3159–67.

    CAS  PubMed  Google Scholar 

  129. Simmons PJ, Aylett GW, Niutta S, To LB, Juttner CA, Ashman LK. c-kit is expressed by primitive human hematopoietic cells that give rise to colony-forming cells in stroma-dependent or cytokine-supplemented culture. Exp Hematol. 1994;22(2):157–65.

    CAS  PubMed  Google Scholar 

  130. Sandlow JI, Feng HL, Cohen MB, Sandra A. Expression of c-KIT and its ligand, stem cell factor, in normal and subfertile human testicular tissue. J Androl. 1996;17(4):403–8.

    CAS  PubMed  Google Scholar 

  131. Wehrle-Haller B, Weston JA. Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development. 1995;121(3):731–42.

    CAS  PubMed  Google Scholar 

  132. Thomsen L, Robinson TL, Lee JC, Farraway LA, Hughes MJ, Andrews DW, Huizinga JD. Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med. 1998;4(7):848–51.

    Article  CAS  PubMed  Google Scholar 

  133. Hosoda T, D’Amario D, Cabral-Da-Silva MC, Zheng H, Padin-Iruegas ME, Ogorek B, Ferreira-Martins J, Yasuzawa-Amano S, Amano K, Ide-Iwata N, Cheng W, Rota M, Urbanek K, Kajstura J, Anversa P, Leri A. Clonality of mouse and human cardiomyogenesis in vivo. Proc Natl Acad Sci U S A. 2009;106(40):17169–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, Smith A, Torella M, Cuellas Ramon C, Gonzalo-Orden JM, Agosti V, Indolfi C, Galiñanes M, Fernandez-Vazquez F, Nadal-Ginard B. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol. 2011;58(9):977–86.

    Article  CAS  PubMed  Google Scholar 

  135. Linke A, Müller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo C, Cascapera S, Böhm M, Quaini F, Urbanek K, Leri A, Hintze TH, Kajstura J, Anversa P. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005;102(25):8966–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fransioli J, Bailey B, Gude NA, Cottage CT, Muraski JA, Emmanuel G, Wu W, Alvarez R, Rubio M, Ottolenghi S, Schaefer E, Sussman MA. Evolution of the c-kit-positive cell response to pathological challenge in the myocardium. Stem Cells. 2008;26(5):1315–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Smith AJ, Lewis FC, Aquila I, Waring CD, Nocera A, Agosti V, Nadal-Ginard B, Torella D, Ellison GM. Isolation and characterization of resident endogenous c-Kit + cardiac stem cells from the adult mouse and rat heart. Nat Protoc. 2014;9(7):1662–81.

    Article  CAS  PubMed  Google Scholar 

  138. Sanada F, Kim J, Czarna A, Chan NY, Signore S, Ogórek B, Isobe K, Wybieralska E, Borghetti G, Pesapane A, Sorrentino A, Mangano E, Cappetta D, Mangiaracina C, Ricciardi M, Cimini M, Ifedigbo E, Perrella MA, Goichberg P, Choi AM, Kajstura J, Hosoda T, Rota M, Anversa P, Leri A. c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res. 2014;114(1):41–55.

    Article  CAS  PubMed  Google Scholar 

  139. Urbanek K, Cesselli D, Rota M, Nascimbene A, De Angelis A, Hosoda T, Bearzi C, Boni A, Bolli R, Kajstura J, Anversa P, Leri A. Stem cell niches in the adult mouse heart. Proc Natl Acad Sci U S A. 2006;103(24):9226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mazhari R, Hare JM. Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche. Nat Clin Pract Cardiovasc Med. 2007;4 Suppl 1:S21–6.

    Article  PubMed  Google Scholar 

  141. Tamplin OJ, Durand EM, Carr LA, Childs SJ, Hagedorn EJ, Li P, Yzaguirre AD, Speck NA, Zon LI. Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell. 2015;160(1-2):241–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505(7483):327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Boulais PE, Frenette PS. Making sense of hematopoietic stem cell niches. Blood. 2015;125(17):2621–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood. 2005;106(6):1901–10.

    Article  CAS  PubMed  Google Scholar 

  145. Taghavi S, George JC. Homing of stem cells to ischemic myocardium. Am J Transl Res. 2013;5(4):404–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Konstandin MH, Toko H, Gastelum GM, Quijada P, De La Torre A, Quintana M, Collins B, Din S, Avitabile D, Völkers M, Gude N, Fässler R, Sussman MA. Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction. Circ Res. 2013;113(2):115–25.

    Article  CAS  PubMed  Google Scholar 

  147. Sturzu AC, Wu SM. Developmental and regenerative biology of multipotent cardiovascular progenitor cells. Circ Res. 2011;108(3):353–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hosoda T, Zheng H, Cabral-da-Silva M, Sanada F, Ide-Iwata N, Ogórek B, Ferreira-Martins J, Arranto C, D’Amario D, del Monte F, Urbanek K, D’Alessandro DA, Michler RE, Anversa P, Rota M, Kajstura J, Leri A. Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation. 2011;123(12):1287–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Fischer KM, Cottage CT, Wu W, Din S, Gude NA, Avitabile D, Quijada P, Collins BL, Fransioli J, Sussman MA. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation. 2009;120(21):2077–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Boni A, Urbanek K, Nascimbene A, Hosoda T, Zheng H, Delucchi F, Amano K, Gonzalez A, Vitale S, Ojaimi C, Rizzi R, Bolli R, Yutzey KE, Rota M, Kajstura J, Anversa P, Leri A. Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci U S A. 2008;105(40):15529–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kwon C, Cheng P, King IN, Andersen P, Shenje L, Nigam V, Srivastava D. Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat Cell Biol. 2011;13(10):1244–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770–6.

    Article  CAS  PubMed  Google Scholar 

  153. Wilson A, Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett. 2006;580(12):2860–8.

    Article  CAS  PubMed  Google Scholar 

  154. Bearzi C, Leri A, Lo Monaco F, Rota M, Gonzalez A, Hosoda T, Pepe M, Qanud K, Ojaimi C, Bardelli S, D’Amario D, D’Alessandro DA, Michler RE, Dimmeler S, Zeiher AM, Urbanek K, Hintze TH, Kajstura J, Anversa P. Identification of a coronary vascular progenitor cell in the human heart. Proc Natl Acad Sci U S A. 2009;106(37):15885–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, Middleton RC, Marbán E, Molkentin JD. c-kit + cells minimally contribute cardiomyocytes to the heart. Nature. 2014;509(7500):337–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Bailey B, Fransioli J, Gude NA, Alvarez Jr R, Zhang X, Gustafsson ÅB, Sussman MA. Sca-1 knockout impairs myocardial and cardiac progenitor cell function. Circ Res. 2012;111(6):750–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Uchida S, De Gaspari P, Kostin S, Jenniches K, Kilic A, Izumiya Y, Shiojima I, Grosse Kreymborg K, Renz H, Walsh K, Braun T. Sca1-derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Rep. 2013;1(5):397–410.

    Article  CAS  Google Scholar 

  158. Smits AM, van Vliet P, Metz CH, Korfage T, Sluijter JP, Doevendans PA, Goumans MJ. Human cardiomyocyte progenitor cells differentiate into functional mature cardiomyocytes: an in vitro model for studying human cardiac physiology and pathophysiology. Nat Protoc. 2009;4(2):232–43.

    Article  CAS  PubMed  Google Scholar 

  159. Smits AM, van Laake LW, den Ouden K, Schreurs C, Szuhai K, van Echteld CJ, Mummery CL, Doevendans PA, Goumans MJ. Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium. Cardiovasc Res. 2009;83(3):527–35.

    Article  CAS  PubMed  Google Scholar 

  160. 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(4):1797–806.

    Article  CAS  PubMed  Google Scholar 

  161. Pfister O, Oikonomopoulos A, Sereti KI, Sohn RL, Cullen D, Fine GC, Mouquet F, Westerman K, Liao R. Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. Circ Res. 2008;103(8):825–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, Colucci WS, Liao R. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res. 2005;97(1):52–61.

    Article  CAS  PubMed  Google Scholar 

  163. Noseda M, Harada M, McSweeney S, Leja T, Belian E, Stuckey DJ, Abreu Paiva MS, Habib J, Macaulay I, de Smith AJ, al-Beidh F, Sampson R, Lumbers RT, Rao P, Harding SE, Blakemore AI, Jacobsen SE, Barahona M, Schneider MD. PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium. Nat Commun. 2015;6:6930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002;530(1-3):239–43.

    Article  CAS  PubMed  Google Scholar 

  165. Oyama T, Nagai T, Wada H, Naito AT, Matsuura K, Iwanaga K, Takahashi T, Goto M, Mikami Y, Yasuda N, Akazawa H, Uezumi A, Takeda S, Komuro I. Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J Cell Biol. 2007;176(3):329–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107(11):1395–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Acharya A, Baek ST, Huang G, Eskiocak B, Goetsch S, Sung CY, Banfi S, Sauer MF, Olsen GS, Duffield JS, Olson EN, Tallquist MD. The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development. 2012;139(12):2139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature. 2004;432(7016):466–72.

    Article  CAS  PubMed  Google Scholar 

  169. Chong JJ, Chandrakanthan V, Xaymardan M, Asli NS, Li J, Ahmed I, Heffernan C, Menon MK, Scarlett CJ, Rashidianfar A, Biben C, Zoellner H, Colvin EK, Pimanda JE, Biankin AV, Zhou B, Pu WT, Prall OW, Harvey RP. Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell. 2011;9(6):527–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ellison GM, Nadal-Ginard B, Torella D. Optimizing cardiac repair and regeneration through activation of the endogenous cardiac stem cell compartment. J Cardiovasc Transl Res. 2012;5(5):667–77.

    Article  PubMed  Google Scholar 

  171. Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res. 2012;110(1):159–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rienks M, Papageorgiou AP, Frangogiannis NG, Heymans S. Myocardial extracellular matrix: an ever-changing and diverse entity. Circ Res. 2014;114(5):872–88.

    Article  CAS  PubMed  Google Scholar 

  173. Waddington CH. Canalization of development, and the inheritance of acquired characters. Nature. 1942;150:563–5.

    Article  Google Scholar 

  174. Davis RL, Cheng PF, Lassar AB, Weintraub H. The MyoD DNA binding domain contains a recognition code for muscle-specific gene activation. Cell. 1990;60(5):733–46.

    Article  CAS  PubMed  Google Scholar 

  175. Black BL, Molkentin JD, Olson EN. Multiple roles for the MyoD basic region in transmission of transcriptional activation signals and interaction with MEF2. Mol Cell Biol. 1998;18(1):69–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  177. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627–32.

    Article  CAS  PubMed  Google Scholar 

  178. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463(7284):1035–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485(7400):599–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, Zhang Z, Rosenberg P, Mirotsou M, Dzau VJ. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110(11):1465–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Lee J, Sayed N, Hunter A, Au KF, Wong WH, Mocarski ES, Pera RR, Yakubov E, Cooke JP. Activation of innate immunity is required for efficient nuclear reprogramming. Cell. 2012;151(3):547–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Wang L, Liu Z, Yin C, Asfour H, Chen O, Li Y, Bursac N, Liu J, Qian L. Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circ Res. 2015;116(2):237–44.

    Article  CAS  PubMed  Google Scholar 

  183. Fu JD, Stone NR, Liu L, Spencer CI, Qian L, Hayashi Y, Delgado-Olguin P, Ding S, Bruneau BG, Srivastava D. Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Rep. 2013;1(3):235–47.

    Article  CAS  Google Scholar 

  184. Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Kaneda R, Suzuki T, Kamiya K, Tohyama S, Yuasa S, Kokaji K, Aeba R, Yozu R, Yamagishi H, Kitamura T, Fukuda K, Ieda M. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A. 2013;110(31):12667–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K, Hill JA, DiMaio JM, Baker LA, Bassel-Duby R, Olson EN. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A. 2013;110(14):5588–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485(7400):593–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Jayawardena TM, Finch EA, Zhang L, Zhang H, Hodgkinson CP, Pratt RE, Rosenberg PB, Mirotsou M, Dzau VJ. MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res. 2015;116(3):418–24.

    Article  CAS  PubMed  Google Scholar 

  188. Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ, Gantz JA, Fugate JA, Muskheli V, Gough GM, Vogel KW, Astley CA, Hotchkiss CE, Baldessari A, Pabon L, Reinecke H, Gill EA, Nelson V, Kiem HP, Laflamme MA, Murry CE. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014;510(7504):273–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Shiba Y, Fernandes S, Zhu WZ, Filice D, Muskheli V, Kim J, Palpant NJ, Gantz J, Moyes KW, Reinecke H, Van Biber B, Dardas T, Mignone JL, Izawa A, Hanna R, Viswanathan M, Gold JD, Kotlikoff MI, Sarvazyan N, Kay MW, Murry CE, Laflamme MA. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature. 2012;489(7415):322–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Ye L, Chang YH, Xiong Q, Zhang P, Zhang L, Somasundaram P, Lepley M, Swingen C, Su L, Wendel JS, Guo J, Jang A, Rosenbush D, Greder L, Dutton JR, Zhang J, Kamp TJ, Kaufman DS, Ge Y, Zhang J. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell. 2014;15(6):750–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Zimmermann WH, Schneiderbanger K, Schubert P, Didié M, Münzel F, Heubach JF, Kostin S, Neuhuber WL, Eschenhagen T. Tissue engineering of a differentiated cardiac muscle construct. Circ Res. 2002;90(2):223–30.

    Article  CAS  PubMed  Google Scholar 

  192. Hansen A, Eder A, Bönstrup M, Flato M, Mewe M, Schaaf S, Aksehirlioglu B, Schwoerer AP, Uebeler J, Eschenhagen T. Development of a drug screening platform based on engineered heart tissue. Circ Res. 2010;107(1):35–44.

    Article  CAS  PubMed  Google Scholar 

  193. Zimmermann WH, Melnychenko I, Wasmeier G, Didié 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(4):452–8.

    Article  CAS  PubMed  Google Scholar 

  194. Shimizu T, Yamato M, Isoi Y, Akutsu T, Setomaru T, Abe K, Kikuchi A, Umezu M, Okano T. 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(3):e40.

    Article  CAS  PubMed  Google Scholar 

  195. Furuta A, Miyoshi S, Itabashi Y, Shimizu T, Kira S, Hayakawa K, Nishiyama N, Tanimoto K, Hagiwara Y, Satoh T, Fukuda K, Okano T, Ogawa S. 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(5):705–12.

    Article  CAS  PubMed  Google Scholar 

  196. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14(2):213–21.

    Article  CAS  PubMed  Google Scholar 

  197. Robertson MJ, Dries-Devlin JL, Kren SM, Burchfield JS, Taylor DA. Optimizing recellularization of whole decellularized heart extracellular matrix. PLoS One. 2014;9(2):e90406.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Ye L, Zimmermann WH, Garry DJ, Zhang J. Patching the heart: cardiac repair from within and outside. Circ Res. 2013;113(7):922–32.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jop H. van Berlo MD, PhD or Daniel J. Garry MD, PhD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

van Berlo, J.H., Garry, M.G., Garry, D.J. (2017). Regenerative Mechanisms of the Adult Injured and Failing Heart. In: Garry, D., Wilson, R., Vlodaver, Z. (eds) Congestive Heart Failure and Cardiac Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-44577-9_23

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-44577-9_23

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-44575-5

  • Online ISBN: 978-3-319-44577-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics