Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Are There Hopeful Therapeutic Strategies to Regenerate the Infarcted Hearts?

  • Gyu-Chul Oh (Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Yeon-Jik Choi (Division of Cardiology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea) ;
  • Bong-Woo Park (Department of Biomedicine & Health Sciences, The Catholic University of Korea) ;
  • Kiwon Ban (Department of Biomedical Sciences, City University of Hong Kong) ;
  • Hun-Jun Park (Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea)
  • Received : 2023.04.10
  • Accepted : 2023.04.26
  • Published : 2023.06.01
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Abstract

Ischemic heart disease remains the primary cause of morbidity and mortality worldwide. Despite significant advancements in pharmacological and revascularization techniques in the late 20th century, heart failure prevalence after myocardial infarction has gradually increased over the last 2 decades. After ischemic injury, pathological remodeling results in cardiomyocytes (CMs) loss and fibrosis, which leads to impaired heart function. Unfortunately, there are no clinical therapies to regenerate CMs to date, and the adult heart's limited turnover rate of CMs hinders its ability to self-regenerate. In this review, we present novel therapeutic strategies to regenerate injured myocardium, including (1) reconstruction of cardiac niche microenvironment, (2) recruitment of functional CMs by promoting their proliferation or differentiation, and (3) organizing 3-dimensional tissue construct beyond the CMs. Additionally, we highlight recent mechanistic insights that govern these strategies and identify current challenges in translating these approaches to human patients.

Keywords

Acknowledgement

This research was supported by Korean Fund for Regenerative Medicine funded by Ministry of Science and ICT, and Ministry of Health and Welfare (21A0104L1-11, Republic of Korea).

References

  1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020;396:1204-22.  https://doi.org/10.1016/S0140-6736(20)30925-9
  2. Jenca D, Melenovsky V, Stehlik J, et al. Heart failure after myocardial infarction: incidence and predictors. ESC Heart Fail 2021;8:222-37.  https://doi.org/10.1002/ehf2.13144
  3. Bhar-Amato J, Davies W, Agarwal S. Ventricular arrhythmia after acute myocardial infarction: 'the perfect storm'. Arrhythm Electrophysiol Rev 2017;6:134-9.  https://doi.org/10.15420/aer.2017.24.1
  4. Roe MT, Messenger JC, Weintraub WS, et al. Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention. J Am Coll Cardiol 2010;56:254-63. https://doi.org/10.1016/j.jacc.2010.05.008
  5. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet 2001;357:279-80.  https://doi.org/10.1016/S0140-6736(00)03617-5
  6. Banerjee MN, Bolli R, Hare JM. Clinical studies of cell therapy in cardiovascular medicine: recent developments and future directions. Circ Res 2018;123:266-87.  https://doi.org/10.1161/CIRCRESAHA.118.311217
  7. Wang Y, Wei J, Zhang P, et al. Neuregulin-1, a potential therapeutic target for cardiac repair. Front Pharmacol 2022;13:945206. 
  8. Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 1997;100:1991-9.  https://doi.org/10.1172/JCI119730
  9. Rasanen M, Sultan I, Paech J, et al. VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration. Circulation 2021;143:65-77.  https://doi.org/10.1161/CIRCULATIONAHA.120.050635
  10. Gwathmey JK, Yerevanian A, Hajjar RJ. Targeting sarcoplasmic reticulum calcium ATPase by gene therapy. Hum Gene Ther 2013;24:937-47.  https://doi.org/10.1089/hum.2013.2512
  11. Lee CS, Kim J, Cho HJ, Kim HS. Cardiovascular regeneration via stem cells and direct reprogramming: a review. Korean Circ J 2022;52:341-53.  https://doi.org/10.4070/kcj.2022.0005
  12. Bui TV, Hwang JW, Lee JH, Park HJ, Ban K. Challenges and limitations of strategies to promote therapeutic potential of human mesenchymal stem cells for cell-based cardiac repair. Korean Circ J 2021;51:97-113.  https://doi.org/10.4070/kcj.2020.0518
  13. Leri A, Rota M, Hosoda T, Goichberg P, Anversa P. Cardiac stem cell niches. Stem Cell Res 2014;13:631-46.  https://doi.org/10.1016/j.scr.2014.09.001
  14. Pries AR, Reglin B. Coronary microcirculatory pathophysiology: can we afford it to remain a black box? Eur Heart J 2017;38:478-88.  https://doi.org/10.1093/eurheartj/ehv760
  15. Rajendran P, Rengarajan T, Thangavel J, et al. The vascular endothelium and human diseases. Int J Biol Sci 2013;9:1057-69.  https://doi.org/10.7150/ijbs.7502
  16. Soares RO, Losada DM, Jordani MC, Evora P, Castro-E-Silva O. Ischemia/reperfusion injury revisited: an overview of the latest pharmacological strategies. Int J Mol Sci 2019;20:5034. 
  17. Oka T, Akazawa H, Naito AT, Komuro I. Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ Res 2014;114:565-71.  https://doi.org/10.1161/CIRCRESAHA.114.300507
  18. van der Laan AM, Piek JJ, van Royen N. Targeting angiogenesis to restore the microcirculation after reperfused MI. Nat Rev Cardiol 2009;6:515-23.  https://doi.org/10.1038/nrcardio.2009.103
  19. Saeed M, Saloner D, Martin A, et al. Adeno-associated viral vector-encoding vascular endothelial growth factor gene: effect on cardiovascular MR perfusion and infarct resorption measurements in swine. Radiology 2007;243:451-60.  https://doi.org/10.1148/radiol.2432060928
  20. Battler A, Scheinowitz M, Bor A, et al. Intracoronary injection of basic fibroblast growth factor enhances angiogenesis in infarcted swine myocardium. J Am Coll Cardiol 1993;22:2001-6.  https://doi.org/10.1016/0735-1097(93)90790-8
  21. Chen XH, Minatoguchi S, Kosai K, et al. In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions. J Card Fail 2007;13:874-83.  https://doi.org/10.1016/j.cardfail.2007.07.004
  22. Saeed M, Martin A, Ursell P, et al. MR assessment of myocardial perfusion, viability, and function after intramyocardial transfer of VM202, a new plasmid human hepatocyte growth factor in ischemic swine myocardium. Radiology 2008;249:107-18.  https://doi.org/10.1148/radiol.2483071579
  23. Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol 2008;28:208-16. https://doi.org/10.1161/ATVBAHA.107.155317
  24. Massa M, Rosti V, Ferrario M, et al. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 2005;105:199-206.  https://doi.org/10.1182/blood-2004-05-1831
  25. Templin C, Kotlarz D, Faulhaber J, et al. Ex vivo expanded hematopoietic progenitor cells improve cardiac function after myocardial infarction: role of beta-catenin transduction and cell dose. J Mol Cell Cardiol 2008;45:394-403.  https://doi.org/10.1016/j.yjmcc.2008.06.010
  26. Halkos ME, Zhao ZQ, Kerendi F, et al. Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol 2008;103:525-36.  https://doi.org/10.1007/s00395-008-0741-0
  27. Schuleri KH, Amado LC, Boyle AJ, et al. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol 2008;294:H2002-11.  https://doi.org/10.1152/ajpheart.00762.2007
  28. Tang J, Xie Q, Pan G, Wang J, Wang M. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur J Cardiothorac Surg 2006;30:353-61.  https://doi.org/10.1016/j.ejcts.2006.02.070
  29. Kanellakis P, Slater NJ, Du XJ, Bobik A, Curtis DJ. Granulocyte colony-stimulating factor and stem cell factor improve endogenous repair after myocardial infarction. Cardiovasc Res 2006;70:117-25.  https://doi.org/10.1016/j.cardiores.2006.01.005
  30. Sato T, Suzuki H, Kusuyama T, et al. G-CSF after myocardial infarction accelerates angiogenesis and reduces fibrosis in swine. Int J Cardiol 2008;127:166-73.  https://doi.org/10.1016/j.ijcard.2007.05.007
  31. Guo Y, He J, Wu J, et al. Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Arch Med Res 2008;39:179-88.  https://doi.org/10.1016/j.arcmed.2007.11.001
  32. Lu F, Zhao X, Wu J, et al. MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis. Int J Cardiol 2013;167:2524-32.  https://doi.org/10.1016/j.ijcard.2012.06.052
  33. Park BW, Jung SH, Das S, et al. In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair. Sci Adv 2020;6:eaay6994. 
  34. Park SJ, Kim RY, Park BW, et al. Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction. Nat Commun 2019;10:3123. 
  35. Han C, Nie Y, Lian H, et al. Acute inflammation stimulates a regenerative response in the neonatal mouse heart. Cell Res 2015;25:1137-51.  https://doi.org/10.1038/cr.2015.110
  36. Godwin JW, Pinto AR, Rosenthal NA. Macrophages are required for adult salamander limb regeneration. Proc Natl Acad Sci U S A 2013;110:9415-20.  https://doi.org/10.1073/pnas.1300290110
  37. King MW, Neff AW, Mescher AL. The developing Xenopus limb as a model for studies on the balance between inflammation and regeneration. Anat Rec (Hoboken) 2012;295:1552-61.  https://doi.org/10.1002/ar.22443
  38. Silvis MJ, Kaffka Genaamd Dengler SE, Odille CA, et al. Damage-associated molecular patterns in myocardial infarction and heart transplantation: the road to translational success. Front Immunol 2020;11:599511. 
  39. Cao DJ, Schiattarella GG, Villalobos E, et al. Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury. Circulation 2018;137:2613-34.  https://doi.org/10.1161/CIRCULATIONAHA.117.031046
  40. Sandanger O, Ranheim T, Vinge LE, et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res 2013;99:164-74.  https://doi.org/10.1093/cvr/cvt091
  41. Kratofil RM, Kubes P, Deniset JF. Monocyte conversion during inflammation and injury. Arterioscler Thromb Vasc Biol 2017;37:35-42. https://doi.org/10.1161/ATVBAHA.116.308198
  42. Kim Y, Nurakhayev S, Nurkesh A, Zharkinbekov Z, Saparov A. Macrophage polarization in cardiac tissue repair following myocardial infarction. Int J Mol Sci 2021;22:2715. 
  43. Shiraishi M, Shintani Y, Shintani Y, et al. Alternatively activated macrophages determine repair of the infarcted adult murine heart. J Clin Invest 2016;126:2151-66.  https://doi.org/10.1172/JCI85782
  44. Lee JR, Park BW, Kim J, et al. Nanovesicles derived from iron oxide nanoparticles-incorporated mesenchymal stem cells for cardiac repair. Sci Adv 2020;6:eaaz0952. 
  45. Zhang H, Kim H, Park BW, et al. CU06-1004 enhances vascular integrity and improves cardiac remodeling by suppressing edema and inflammation in myocardial ischemia-reperfusion injury. Exp Mol Med 2022;54:23-34.  https://doi.org/10.1038/s12276-021-00720-w
  46. Su Y, Gao J, Kaur P, Wang Z. Neutrophils and macrophages as targets for development of nanotherapeutics in inflammatory diseases. Pharmaceutics 2020;12:1222. 
  47. Forte E, Perkins B, Sintou A, et al. Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart. Circulation 2021;143:821-36.  https://doi.org/10.1161/CIRCULATIONAHA.120.044581
  48. Bansal SS, Ismahil MA, Goel M, et al. Dysfunctional and proinflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy. Circulation 2019;139:206-21.  https://doi.org/10.1161/CIRCULATIONAHA.118.036065
  49. Srenathan U, Steel K, Taams LS. IL-17+ CD8+ T cells: differentiation, phenotype and role in inflammatory disease. Immunol Lett 2016;178:20-6.  https://doi.org/10.1016/j.imlet.2016.05.001
  50. Bansal SS, Ismahil MA, Goel M, et al. Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure. Circ Heart Fail 2017;10:e003688. 
  51. Choo EH, Lee JH, Park EH, et al. Infarcted myocardium-primed dendritic cells improve remodeling and cardiac function after myocardial infarction by modulating the regulatory T cell and macrophage polarization. Circulation 2017;135:1444-57.  https://doi.org/10.1161/CIRCULATIONAHA.116.023106
  52. Rieckmann M, Delgobo M, Gaal C, et al. Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses. J Clin Invest 2019;129:4922-36.  https://doi.org/10.1172/JCI123859
  53. Weirather J, Hofmann UD, Beyersdorf N, et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 2014;115:55-67.  https://doi.org/10.1161/CIRCRESAHA.115.303895
  54. Kalkman EA, van Suylen RJ, van Dijk JP, Saxena PR, Schoemaker RG. Chronic aspirin treatment affects collagen deposition in non-infarcted myocardium during remodeling after coronary artery ligation in the rat. J Mol Cell Cardiol 1995;27:2483-94.  https://doi.org/10.1006/jmcc.1995.0236
  55. Lefer AM, Polansky EW. Beneficial effects of ibuprofen in acute myocardial ischemia. Cardiology 1979;64:265-79.  https://doi.org/10.1159/000170624
  56. Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 2014;16:821-47.  https://doi.org/10.18433/J3VW2F
  57. Gao R, Shi H, Chang S, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. Int Immunopharmacol 2019;74:105575. 
  58. Fung TH, Yang KY, Lui KO. An emerging role of regulatory T-cells in cardiovascular repair and regeneration. Theranostics 2020;10:8924-38.  https://doi.org/10.7150/thno.47118
  59. Wirrig EE, Snarr BS, Chintalapudi MR, et al. Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development. Dev Biol 2007;310:291-303.  https://doi.org/10.1016/j.ydbio.2007.07.041
  60. Bassat E, Mutlak YE, Genzelinakh A, et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 2017;547:179-84. https://doi.org/10.1038/nature22978
  61. Baehr A, Umansky KB, Bassat E, et al. Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs. Circulation 2020;142:868-81.  https://doi.org/10.1161/CIRCULATIONAHA.119.045116
  62. Chen Z, Xie J, Hao H, et al. Ablation of periostin inhibits post-infarction myocardial regeneration in neonatal mice mediated by the phosphatidylinositol 3 kinase/glycogen synthase kinase 3β/cyclin D1 signalling pathway. Cardiovasc Res 2017;113:620-32.  https://doi.org/10.1093/cvr/cvx001
  63. Kuhn B, del Monte F, Hajjar RJ, et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med 2007;13:962-9.  https://doi.org/10.1038/nm1619
  64. Ladage D, Yaniz-Galende E, Rapti K, et al. Stimulating myocardial regeneration with periostin Peptide in large mammals improves function post-myocardial infarction but increases myocardial fibrosis. PLoS One 2013;8:e59656. 
  65. Giacca M, Zacchigna S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther 2012;19:622-9.  https://doi.org/10.1038/gt.2012.17
  66. Del Monte-Nieto G, Fischer JW, Gorski DJ, Harvey RP, Kovacic JC. Basic biology of extracellular matrix in the cardiovascular system, part 1/4: JACC focus seminar. J Am Coll Cardiol 2020;75:2169-88.  https://doi.org/10.1016/j.jacc.2020.03.024
  67. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014;15:786-801.  https://doi.org/10.1038/nrm3904
  68. Seif-Naraghi SB, Singelyn JM, Salvatore MA, et al. Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction. Sci Transl Med 2013;5:173ra25. 
  69. Singelyn JM, Sundaramurthy P, Johnson TD, et al. Catheter-deliverable hydrogel derived from decellularized ventricular extracellular matrix increases endogenous cardiomyocytes and preserves cardiac function post-myocardial infarction. J Am Coll Cardiol 2012;59:751-63.  https://doi.org/10.1016/j.jacc.2011.10.888
  70. Wassenaar JW, Gaetani R, Garcia JJ, et al. Evidence for mechanisms underlying the functional benefits of a myocardial matrix hydrogel for post-MI treatment. J Am Coll Cardiol 2016;67:1074-86.  https://doi.org/10.1016/j.jacc.2015.12.035
  71. Korf-Klingebiel M, Reboll MR, Grote K, et al. Heparan sulfate-editing extracellular sulfatases enhance VEGF bioavailability for ischemic heart repair. Circ Res 2019;125:787-801.  https://doi.org/10.1161/CIRCRESAHA.119.315023
  72. Mukherjee D, Wagh G, Mokalled MH, et al. Ccn2a is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish. Development 2021;148:dev193219. 
  73. Notari M, Ventura-Rubio A, Bedford-Guaus SJ, et al. The local microenvironment limits the regenerative potential of the mouse neonatal heart. Sci Adv 2018;4:eaao5553. 
  74. Perestrelo AR, Silva AC, Oliver-De La Cruz J, et al. Multiscale analysis of extracellular matrix remodeling in the failing heart. Circ Res 2021;128:24-38.  https://doi.org/10.1161/CIRCRESAHA.120.317685
  75. Corbin EA, Vite A, Peyster EG, et al. Tunable and reversible substrate stiffness reveals a dynamic mechanosensitivity of cardiomyocytes. ACS Appl Mater Interfaces 2019;11:20603-14.  https://doi.org/10.1021/acsami.9b02446
  76. Yahalom-Ronen Y, Rajchman D, Sarig R, Geiger B, Tzahor E. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. Elife 2015;4:e07455. 
  77. Traverse JH, Henry TD, Dib N, et al. First-in-man study of a cardiac extracellular matrix hydrogel in early and late myocardial infarction patients. JACC Basic Transl Sci 2019;4:659-69.  https://doi.org/10.1016/j.jacbts.2019.07.012
  78. Walsh S, Ponten A, Fleischmann BK, Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo--an analysis based on cardiomyocyte nuclei. Cardiovasc Res 2010;86:365-73.  https://doi.org/10.1093/cvr/cvq005
  79. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009;324:98-102. https://doi.org/10.1126/science.1164680
  80. Bergmann O, Zdunek S, Felker A, et al. Dynamics of cell generation and turnover in the human heart. Cell 2015;161:1566-75.  https://doi.org/10.1016/j.cell.2015.05.026
  81. Porrello ER, Olson EN. A neonatal blueprint for cardiac regeneration. Stem Cell Res 2014;13:556-70.  https://doi.org/10.1016/j.scr.2014.06.003
  82. Kikuchi K, Holdway JE, Werdich AA, et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 2010;464:601-5.  https://doi.org/10.1038/nature08804
  83. Schindler YL, Garske KM, Wang J, et al. Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration. Development 2014;141:3112-22.  https://doi.org/10.1242/dev.106336
  84. Muralidhar SA, Sadek HA. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. In: Nakanishi T, Markwald RR, Baldwin HS, et al., editors. Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology. Tokyo: Springer Tokyo; 2016. p.93-101.
  85. Pesce M, Burba I, Gambini E, Prandi F, Pompilio G, Capogrossi MC. Endothelial and cardiac progenitors: boosting, conditioning and (re)programming for cardiovascular repair. Pharmacol Ther 2011;129:50-61.  https://doi.org/10.1016/j.pharmthera.2010.10.003
  86. Halder G, Johnson RL. Hippo signaling: growth control and beyond. Development 2011;138:9-22.  https://doi.org/10.1242/dev.045500
  87. Varelas X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 2014;141:1614-26.  https://doi.org/10.1242/dev.102376
  88. Zheng M, Jacob J, Hung SH, Wang J. The Hippo pathway in cardiac regeneration and homeostasis: new perspectives for cell-free therapy in the injured heart. Biomolecules 2020;10:1024. 
  89. Leach JP, Heallen T, Zhang M, et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 2017;550:260-4.  https://doi.org/10.1038/nature24045
  90. Lin Z, von Gise A, Zhou P, et al. Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ Res 2014;115:354-63.  https://doi.org/10.1161/CIRCRESAHA.115.303632
  91. Morikawa Y, Heallen T, Leach J, Xiao Y, Martin JF. Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 2017;547:227-31.  https://doi.org/10.1038/nature22979
  92. Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003;284:14-30.  https://doi.org/10.1016/S0014-4827(02)00102-7
  93. Del Monte-Nieto G, Ramialison M, Adam AA, et al. Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature 2018;557:439-45.  https://doi.org/10.1038/s41586-018-0110-6
  94. Baliga RR, Pimental DR, Zhao YY, et al. NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70(S6K), and MEK-MAPK-RSK. Am J Physiol 1999;277:H2026-37.  https://doi.org/10.1152/ajpheart.1999.277.5.H2026
  95. Reischauer S, Arnaout R, Ramadass R, Stainier DY. Actin binding GFP allows 4D in vivo imaging of myofilament dynamics in the zebrafish heart and the identification of Erbb2 signaling as a remodeling factor of myofibril architecture. Circ Res 2014;115:845-56.  https://doi.org/10.1161/CIRCRESAHA.115.304356
  96. Gemberling M, Karra R, Dickson AL, Poss KD. Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. Elife 2015;4:e05871. 
  97. de Bakker DE, Bouwman M, Dronkers E, et al. Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration. Development 2021;148:dev198937. 
  98. Bersell K, Arab S, Haring B, Kuhn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 2009;138:257-70.  https://doi.org/10.1016/j.cell.2009.04.060
  99. D'Uva G, Aharonov A, Lauriola M, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 2015;17:627-38. https://doi.org/10.1038/ncb3149
  100. Aharonov A, Shakked A, Umansky KB, et al. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat Cell Biol 2020;22:1346-56.  https://doi.org/10.1038/s41556-020-00588-4
  101. Denning C, Borgdorff V, Crutchley J, et al. Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta 2016;1863:1728-48.  https://doi.org/10.1016/j.bbamcr.2015.10.014
  102. Shiba Y. Pluripotent stem cells for cardiac regeneration-current status, challenges, and future perspectives-. Circ J 2020;84:2129-35.  https://doi.org/10.1253/circj.CJ-20-0755
  103. Park SJ, Kim H, Lee S, et al. Effect and application of cryopreserved three-dimensional microcardiac spheroids in myocardial infarction therapy. Clin Transl Med 2022;12:e721. 
  104. Chong JJ, Yang X, Don CW, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate nonhuman primate hearts. Nature 2014;510:273-7.  https://doi.org/10.1038/nature13233
  105. Liu YW, Chen B, Yang X, et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol 2018;36:597-605.  https://doi.org/10.1038/nbt.4162
  106. Huch M, Koo BK. Modeling mouse and human development using organoid cultures. Development 2015;142:3113-25.  https://doi.org/10.1242/dev.118570
  107. Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol 2016;18:246-54.  https://doi.org/10.1038/ncb3312
  108. Kupfer ME, Lin WH, Ravikumar V, et al. In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid. Circ Res 2020;127:207-24.  https://doi.org/10.1161/CIRCRESAHA.119.316155
  109. Lee J, Sutani A, Kaneko R, et al. In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix. Nat Commun 2020;11:4283. 
  110. Wu CC, Jeratsch S, Graumann J, Stainier DY. Modulation of mammalian cardiomyocyte cytokinesis by the extracellular matrix. Circ Res 2020;127:896-907.  https://doi.org/10.1161/CIRCRESAHA.119.316303
  111. Li Y, Asfour H, Bursac N. Age-dependent functional crosstalk between cardiac fibroblasts and cardiomyocytes in a 3D engineered cardiac tissue. Acta Biomater 2017;55:120-30.  https://doi.org/10.1016/j.actbio.2017.04.027
  112. Mastikhina O, Moon BU, Williams K, et al. Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing. Biomaterials 2020;233:119741. 
  113. Sekine H, Shimizu T, Hobo K, et al. Endothelial cell coculture within tissue-engineered cardiomyocyte sheets enhances neovascularization and improves cardiac function of ischemic hearts. Circulation 2008;118:S145-52.  https://doi.org/10.1161/CIRCULATIONAHA.107.757286
  114. Choi A, Kim H, Han H, et al. Sutureless transplantation of in vivo priming human mesenchymal stem cell sheet promotes the therapeutic potential for cardiac repair. Biofabrication 2023;15:015009. 
  115. Giacomelli E, Meraviglia V, Campostrini G, et al. Human-iPSC-derived cardiac stromal cells enhance maturation in 3D cardiac microtissues and reveal non-cardiomyocyte contributions to heart disease. Cell Stem Cell 2020;26:862-879.e11.  https://doi.org/10.1016/j.stem.2020.05.004
  116. Lesman A, Habib M, Caspi O, et al. Transplantation of a tissue-engineered human vascularized cardiac muscle. Tissue Eng Part A 2010;16:115-25.  https://doi.org/10.1089/ten.tea.2009.0130
  117. Ishigami M, Masumoto H, Ikuno T, et al. Human iPS cell-derived cardiac tissue sheets for functional restoration of infarcted porcine hearts. PLoS One 2018;13:e0201650. 
  118. Huang K, Ozpinar EW, Su T, et al. An off-the-shelf artificial cardiac patch improves cardiac repair after myocardial infarction in rats and pigs. Sci Transl Med 2020;12:eaat9683.
  119. Gaetani R, Doevendans PA, Metz CH, et al. Cardiac tissue engineering using tissue printing technology and human cardiac progenitor cells. Biomaterials 2012;33:1782-90.  https://doi.org/10.1016/j.biomaterials.2011.11.003
  120. Gaetani R, Feyen DA, Verhage V, et al. Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction. Biomaterials 2015;61:339-48.  https://doi.org/10.1016/j.biomaterials.2015.05.005
  121. Ong CS, Fukunishi T, Zhang H, et al. Biomaterial-free three-dimensional bioprinting of cardiac tissue using human induced pluripotent stem cell derived cardiomyocytes. Sci Rep 2017;7:4566.