Pediatric Cardiology

, Volume 40, Issue 7, pp 1359–1366 | Cite as

Phases and Mechanisms of Embryonic Cardiomyocyte Proliferation and Ventricular Wall Morphogenesis

  • Yaacov Barak
  • Myriam Hemberger
  • Henry M. SucovEmail author
Riley Symposium


If viewed as a movie, heart morphogenesis appears to unfold in a continuous and seamless manner. At the mechanistic level, however, a series of discreet and separable processes sequentially underlie heart development. This is evident in examining the expansion of the ventricular wall, which accounts for most of the contractile force of each heartbeat. Ventricular wall expansion is driven by cardiomyocyte proliferation coupled with a morphogenetic program that causes wall thickening rather than lengthening. Although most studies of these processes have focused on heart-intrinsic processes, it is increasingly clear that extracardiac events influence or even direct heart morphogenesis. In this review, we specifically consider mechanisms responsible for coordinating cardiomyocyte proliferation and ventricular wall expansion in mammalian development, relying primarily on studies from mouse development where a wealth of molecular and genetic data have been accumulated.


Cardiomyocyte proliferation Epicardium Placenta–heart IGF2 Congenital heart defects 



This review was supported in part by The Magee Prize, Grant #MP001, from the Magee-Womens Research Institute and the Richard King Mellon Foundation, given to YB, MH, and HMS, and by NIH Grant HL070123 provided to HMS.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical Approval

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


  1. 1.
    Kelly RG, Buckingham ME (2002) The anterior heart-forming field: voyage to the arterial pole of the heart. Trends Genet 18:210–216PubMedGoogle Scholar
  2. 2.
    Del Monte-Nieto G, Ramialison M, Adam AAS, Wu B, Aharonov A, D'Uva G, Bourke LM, Pitulescu ME, Chen H, de la Pompa JL, Shou W, Adams RH, Harten SK, Tzahor E, Zhou B, Harvey RP (2018) Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature 557:439–445PubMedGoogle Scholar
  3. 3.
    Wu M (2018) Mechanisms of trabecular formation and specification during cardiogenesis. Pediatr Cardiol 39:1082–1089PubMedPubMedCentralGoogle Scholar
  4. 4.
    Li F, Wang X, Capasso JM, Gerdes AM (1996) Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol 28:1737–1746PubMedGoogle Scholar
  5. 5.
    Foglia MJ, Poss KD (2016) Building and re-building the heart by cardiomyocyte proliferation. Development 143:729–740PubMedPubMedCentralGoogle Scholar
  6. 6.
    Tian X, Hu T, Zhang H, He L, Huang X, Liu Q, Yu W, He L, Yang Z, Yan Y, Yang X, Zhong TP, Pu WT, Zhou B (2014) Vessel formation. De novo formation of a distinct coronary vascular population in neonatal heart. Science 345:90–94PubMedPubMedCentralGoogle Scholar
  7. 7.
    Manner J (1993) Experimental study on the formation of the epicardium in chick embryos. Anat Embryol (Berl) 187:281–289Google Scholar
  8. 8.
    Sengbusch JK, He W, Pinco KA, Yang JT (2002) Dual functions of [alpha]4[beta]1 integrin in epicardial development: initial migration and long-term attachment. J Cell Biol 157:873–882PubMedPubMedCentralGoogle Scholar
  9. 9.
    Gittenberger-de Groot AC, Vrancken Peeters MP, Bergwerff M, Mentink MM, Poelmann RE (2000) Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation. Circ Res 87:969–971PubMedGoogle Scholar
  10. 10.
    Rossant J (1996) Mouse mutants and cardiac development: new molecular insights into cardiogenesis. Circ Res 78:349–353PubMedGoogle Scholar
  11. 11.
    Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E, Geng Y, Yu Q, Bhattacharya S, Bronson RT, Akashi K, Sicinski P (2004) Mouse development and cell proliferation in the absence of D-cyclins. Cell 118:477–491PubMedGoogle Scholar
  12. 12.
    Berthet C, Klarmann KD, Hilton MB, Suh HC, Keller JR, Kiyokawa H, Kaldis P (2006) Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Dev Cell 10:563–573PubMedGoogle Scholar
  13. 13.
    Koera K, Nakamura K, Nakao K, Miyoshi J, Toyoshima K, Hatta T, Otani H, Aiba A, Katsuki M (1997) K-ras is essential for the development of the mouse embryo. Oncogene 15:1151–1159PubMedGoogle Scholar
  14. 14.
    Moens CB, Stanton BR, Parada LF, Rossant J (1993) Defects in heart and lung development in compound heterozygotes for two different targeted mutations at the N-myc locus. Development 119:485–499PubMedGoogle Scholar
  15. 15.
    Chen T, Chang TC, Kang JO, Choudhary B, Makita T, Tran CM, Burch JB, Eid H, Sucov HM (2002) Epicardial induction of fetal cardiomyocyte proliferation via a retinoic acid-inducible trophic factor. Dev Biol 250:198–207PubMedGoogle Scholar
  16. 16.
    Li P, Cavallero S, Gu Y, Chen TH, Hughes J, Hassan AB, Bruning JC, Pashmforoush M, Sucov HM (2011) IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development. Development 138:1795–1805PubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang K, Shen H, Gan P, Cavallero S, Kumar SR, Lien CL, Sucov HM (2019) Differential roles of insulin like growth factor 1 receptor and insulin receptor during embryonic heart development. BMC Dev Biol 19:5PubMedPubMedCentralGoogle Scholar
  18. 18.
    Shen H, Cavallero S, Estrada KD, Sandovici I, Kumar SR, Makita T, Lien CL, Constancia M, Sucov HM (2015) Extracardiac control of embryonic cardiomyocyte proliferation and ventricular wall expansion. Cardiovasc Res 105:271–278PubMedPubMedCentralGoogle Scholar
  19. 19.
    Caron KM, Smithies O (2001) Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene. Proc Natl Acad Sci USA 98:615–619PubMedGoogle Scholar
  20. 20.
    Brade T, Kumar S, Cunningham TJ, Chatzi C, Zhao X, Cavallero S, Li P, Sucov HM, Ruiz-Lozano P, Duester G (2011) Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2. Development 138:139–148PubMedPubMedCentralGoogle Scholar
  21. 21.
    Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML (1999) Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development 126:3597–3605PubMedGoogle Scholar
  22. 22.
    Makita T, Hernandez-Hoyos G, Chen TH, Wu H, Rothenberg EV, Sucov HM (2001) A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes Dev 15:889–901PubMedPubMedCentralGoogle Scholar
  23. 23.
    Makita T, Duncan SA, Sucov HM (2005) Retinoic acid, hypoxia, and GATA factors cooperatively control the onset of fetal liver erythropoietin expression and erythropoietic differentiation. Dev Biol 280:59–72PubMedGoogle Scholar
  24. 24.
    Wessels A, Perez-Pomares JM (2004) The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells. Anat Rec A Discov Mol Cell Evol Biol 276:43–57PubMedGoogle Scholar
  25. 25.
    Yamaguchi Y, Cavallero S, Patterson M, Shen H, Xu J, Kumar SR, Sucov HM (2015) Adipogenesis and epicardial adipose tissue: a novel fate of the epicardium induced by mesenchymal transformation and PPARgamma activation. Proc Natl Acad Sci USA 112:2070–2075PubMedGoogle Scholar
  26. 26.
    Cavallero S, Shen H, Yi C, Lien CL, Kumar SR, Sucov HM (2015) CXCL12 Signaling is essential for maturation of the ventricular coronary endothelial plexus and establishment of functional coronary circulation. Dev Cell 33:469–477PubMedPubMedCentralGoogle Scholar
  27. 27.
    Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM, Srivastava D (2009) Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 16:233–244PubMedPubMedCentralGoogle Scholar
  28. 28.
    Rumyantsev PP (1977) Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol 51:186–273PubMedGoogle Scholar
  29. 29.
    Red-Horse K, Ueno H, Weissman IL, Krasnow MA (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464:549–553PubMedPubMedCentralGoogle Scholar
  30. 30.
    Viragh S, Challice CE (1981) The origin of the epicardium and the embryonic myocardial circulation in the mouse. Anat Rec 201:157–168PubMedGoogle Scholar
  31. 31.
    Jones HN, Olbrych SK, Smith KL, Cnota JF, Habli M, Ramos-Gonzales O, Owens KJ, Hinton AC, Polzin WJ, Muglia LJ, Hinton RB (2015) Hypoplastic left heart syndrome is associated with structural and vascular placental abnormalities and leptin dysregulation. Placenta 36:1078–1086PubMedPubMedCentralGoogle Scholar
  32. 32.
    Matthiesen NB, Henriksen TB, Agergaard P, Gaynor JW, Bach CC, Hjortdal VE, Ostergaard JR (2016) Congenital heart defects and indices of placental and fetal growth in a nationwide study of 924 422 liveborn infants. Circulation 134:1546–1556PubMedGoogle Scholar
  33. 33.
    Rychik J, Goff D, McKay E, Mott A, Tian Z, Licht DJ, Gaynor JW (2018) Characterization of the placenta in the newborn with congenital heart disease: distinctions based on type of cardiac malformation. Pediatr Cardiol 39:1165–1171PubMedPubMedCentralGoogle Scholar
  34. 34.
    Perez-Garcia V, Fineberg E, Wilson R, Murray A, Mazzeo CI, Tudor C, Sienerth A, White JK, Tuck E, Ryder EJ, Gleeson D, Siragher E, Wardle-Jones H, Staudt N, Wali N, Collins J, Geyer S, Busch-Nentwich EM, Galli A, Smith JC, Robertson E, Adams DJ, Weninger WJ, Mohun T, Hemberger M (2018) Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature 555:463–468PubMedPubMedCentralGoogle Scholar
  35. 35.
    Kwee L, Baldwin HS, Shen HM, Stewart CL, Buck C, Buck CA, Labow MA (1995) Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development 121:489–503PubMedGoogle Scholar
  36. 36.
    Yang JT, Rayburn H, Hynes RO (1995) Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 121:549–560PubMedGoogle Scholar
  37. 37.
    Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM (1999) PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4:585–595PubMedGoogle Scholar
  38. 38.
    Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, Valladares A, Perez L, Klein R, Nebreda AR (2000) Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell 6:109–116PubMedGoogle Scholar
  39. 39.
    Hatano N, Mori Y, Oh-hora M, Kosugi A, Fujikawa T, Nakai N, Niwa H, Miyazaki J, Hamaoka T, Ogata M (2003) Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells 8:847–856PubMedGoogle Scholar
  40. 40.
    Dubois NC, Adolphe C, Ehninger A, Wang RA, Robertson EJ, Trumpp A (2008) Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function. Development 135:2455–2465PubMedGoogle Scholar
  41. 41.
    Maruyama EO, Lin H, Chiu SY, Yu HM, Porter GA, Hsu W (2016) Extraembryonic but not embryonic SUMO-specific protease 2 is required for heart development. Sci Rep 6:20999PubMedPubMedCentralGoogle Scholar
  42. 42.
    Langford MB, Outhwaite JE, Hughes M, Natale DRC, Simmons DG (2018) Deletion of the Syncytin A receptor Ly6e impairs syncytiotrophoblast fusion and placental morphogenesis causing embryonic lethality in mice. Sci Rep 8:3961PubMedPubMedCentralGoogle Scholar
  43. 43.
    Hayashi S, Lewis P, Pevny L, McMahon AP (2002) Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain. Mech Dev 119(Suppl 1):S97–S101PubMedGoogle Scholar
  44. 44.
    Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, Evans RM (1994) RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev 8:1007–1018PubMedGoogle Scholar
  45. 45.
    Tran CM, Sucov HM (1998) The RXRalpha gene functions in a non-cell-autonomous manner during mouse cardiac morphogenesis. Development 125:1951–1956PubMedGoogle Scholar
  46. 46.
    Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R, Evans RM (2002) Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci USA 99:303–308PubMedGoogle Scholar
  47. 47.
    Sapin V, Dolle P, Hindelang C, Kastner P, Chambon P (1997) Defects of the chorioallantoic placenta in mouse RXRalpha null fetuses. Dev Biol 191:29–41PubMedGoogle Scholar
  48. 48.
    Wendling O, Chambon P, Mark M (1999) Retinoid X receptors are essential for early mouse development and placentogenesis. Proc Natl Acad Sci USA 96:547–551PubMedGoogle Scholar
  49. 49.
    Thornburg KL, Louey S, Giraud GD (2008) The role of growth in heart development. Nestle Nutr Workshop Ser Pediatr Program 61:39–51PubMedGoogle Scholar
  50. 50.
    Yuan XJ, Tod ML, Rubin LJ, Blaustein MP (1995) Hypoxic and metabolic regulation of voltage-gated K+ channels in rat pulmonary artery smooth muscle cells. Exp Physiol 80:803–813PubMedGoogle Scholar
  51. 51.
    Costa MA (2016) The endocrine function of human placenta: an overview. Reprod Biomed Online 32:14–43PubMedGoogle Scholar
  52. 52.
    Parikh A, Wu J, Blanton RM, Tzanakakis ES (2015) Signaling pathways and gene regulatory networks in cardiomyocyte differentiation. Tissue Eng B 21:377–392Google Scholar
  53. 53.
    Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104:933–942PubMedGoogle Scholar
  54. 54.
    Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080PubMedPubMedCentralGoogle Scholar
  55. 55.
    Robledo M (1956) Myocardial regeneration in young rats. Am J Pathol 32:1215–1239PubMedPubMedCentralGoogle Scholar
  56. 56.
    Ye L, D'Agostino G, Loo SJ, Wang CX, Su LP, Tan SH, Tee GZ, Pua CJ, Pena EM, Cheng RB, Chen WC, Abdurrachim D, Lalic J, Tan RS, Lee TH, Zhang J, Cook SA (2018) Early regenerative capacity in the porcine heart. Circulation 138:2798–2808PubMedGoogle Scholar
  57. 57.
    Zhu W, Zhang E, Zhao M, Chong Z, Fan C, Tang Y, Hunter JD, Borovjagin AV, Walcott GP, Chen JY, Qin G, Zhang J (2018) Regenerative potential of neonatal porcine hearts. Circulation 138:2809–2816PubMedGoogle Scholar
  58. 58.
    Haubner BJ, Schneider J, Schweigmann U, Schuetz T, Dichtl W, Velik-Salchner C, Stein JI, Penninger JM (2016) Functional recovery of a human neonatal heart after severe myocardial infarction. Circ Res 118:216–221PubMedGoogle Scholar
  59. 59.
    Westaby S, Archer N, Myerson SG (2008) Cardiac development after salvage partial left ventriculectomy in an infant with anomalous left coronary artery from the pulmonary artery. J Thorac Cardiovasc Surg 136:784–785PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research InstituteUniversity of PittsburghPittsburghUSA
  2. 2.Departments of Biochemistry & Molecular Biology and Medical Genetics, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
  3. 3.Department of Regenerative Medicine and Cell Biology, and Division of Cardiology, Department of MedicineMedical University of South CarolinaCharlestonUSA

Personalised recommendations