How can the adult zebrafish and neonatal mice teach us about stimulating cardiac regeneration in the human heart?

Papers of special note have been highlighted as: • of interest

References

• 1. Laflamme MA, Murry CE. Heart regeneration. Nature 473(7347), 326–335 (2011).
  Medline CASGoogle Scholar
• 2. Torabi A, Cleland JG, Rigby AS, Sherwi N. Development and course of heart failure after a myocardial infarction in younger and older people. J. Geriatr. Cardiol. 11(1), 1–12 (2014).
  MedlineGoogle Scholar
• 3. Drexler H, Fuchs M. Current limitations in treatment of heart failure: new avenues and treatment options. J. Cardiovasc. Electrophysiol. 13(Suppl. 1), S53–6 (2002).
  MedlineGoogle Scholar
• 4. Tonsho M, Michel S, Ahmed Z et al. Heart transplantation: challenges facing the field. Cold Spring Harb. Perspect. Med. 4(5), a015636 (2014).
  MedlineGoogle Scholar
• 5. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science 298(5601), 2188–90 (2002).
  Medline CASGoogle Scholar
• 6. Porrello ER, Mahmoud AI, Simpson E et al. Transient regenerative potential of the neonatal mouse heart. Science 331(6020), 1078–1080 (2011).
  Medline CASGoogle Scholar
• 7. González-Rosa JM, Martín V, Peralta M et al. Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development 138(9), 1663–1674 (2011).
  Medline CASGoogle Scholar
• 8. González-Rosa JM, Mercader N. Cryoinjury as a myocardial infarction model for the study of cardiac regeneration in the zebrafish. Nat. Protoc. 7(4), 782–788 (2012).
  Medline CASGoogle Scholar
• 9. Wang J, Panáková D, Kikuchi K et al. The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion. Development 138(16), 3421–3430 (2011).
  Medline CASGoogle Scholar
• 10. Mukherjee D, Wagh G, Mokalled MH et al. Ccn2a is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish. Development 148(2), dev193219 (2021).
  Medline CASGoogle Scholar
• 11. Raya A, Koth CM, Büscher D et al. Activation of Notch signaling pathway precedes heart regeneration in zebrafish. Proc. Natl Acad. Sci. USA 100, 11889–95 (2003).
  Medline CASGoogle Scholar
• 12. Chablais F, Veit J, Rainer G, Jaźwińska A. The zebrafish heart regenerates after cryoinjury-induced myocardial infarction. BMC Dev. Biol. 11(1), 1–13 (2011).
  MedlineGoogle Scholar
• 13. Schnabel K, Wu C-C, Kurth T, Weidinger G. Regeneration of cryoinjury induced necrotic heart lesions in zebrafish is associated with epicardial activation and cardiomyocyte proliferation. PLOS ONE 6 (4), e18503 (2011).
  Medline CASGoogle Scholar
• 14. Curado S, Anderson RM, Jungblut B et al. Conditional targeted cell ablation in zebrafish: a new tool for regeneration studies. Dev. Dyn. 236(4), 1025–1035 (2007).
  Medline CASGoogle Scholar
• 15. Sun F, Shoffner AR, Poss KD. A genetic cardiomyocyte ablation model for the study of heart regeneration in zebrafish. Cardiac Regeneration 2158, 71–80 (2021).
  CASGoogle Scholar
• 16. Missinato MA, Zuppo DA, Watkins SC et al. Zebrafish heart regenerates after chemoptogenetic cardiomyocyte depletion. Dev. Dyn. 250(7), 986–1000 (2021).
  Medline CASGoogle Scholar
• 17. Kolk MVV, Meyberg D, Deuse T et al. LAD-ligation: a murine model of myocardial infarction. J. Vis. Exp. 32(14), 1438 (2009).
  Google Scholar
• 18. Haubner BJ, Adamowicz-Brice M, Khadayate S et al. Complete cardiac regeneration in a mouse model of myocardial infarction. Aging 4(12), 966 (2012).
  Medline CASGoogle Scholar
• 19. Haubner BJ, Schuetz T, Penninger JM. A reproducible protocol for neonatal ischemic injury and cardiac regeneration in neonatal mice. Basic Res. Cardiol. 111(6), 64 (2016).
  MedlineGoogle Scholar
• 20. Liu C, Wang L, Wang X, Hou X. A complete heart regeneration model with inflammation as a key component. Exp. Anim. 70(4), 479–487 (2021).
  Medline CASGoogle Scholar
• 21. Li F, Wang X, Capasso JM, Gerdes AM. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J. Mol. Cell. Cardiol. 28(8), 1737–1746 (1996).
  Medline CASGoogle Scholar
• 22. Yutzey KE. Cardiomyocyte Proliferation: Teaching an Old Dogma New Tricks. Circ. Res. 120(4), 627–629 (2017).
  Medline CASGoogle Scholar
• 23. Bergmann O, Bhardwaj RD, Bernard S et al. Evidence for cardiomyocyte renewal in humans. Science 324(5923), 98–102 (2009).
  Medline CASGoogle Scholar
• 24. Patterson M, Barske L, Van Handel B et al. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat. Genet. 49(9), 1346–1353 (2017).
  Medline CASGoogle Scholar
• 25. Alkass K, Panula J, Westman M et al. No evidence for cardiomyocyte number expansion in preadolescent mice. Cell 163(4), 1026–1036 (2015).
  Medline CASGoogle Scholar
• 26. González-Rosa JM, Sharpe M, Field D et al. Myocardial polyploidization creates a barrier to heart regeneration in zebrafish. Dev. Cell 44(4), 433–446.e7 (2018).
  Medline CASGoogle Scholar
• 27. Adler CP, Friedburg H, Herget GW et al. Variability of cardiomyocyte DNA content, ploidy level and nuclear number in mammalian hearts. Virchows Arch. 429(2-3), 159–164 (1996).
  Medline CASGoogle Scholar
• 28. 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. 36(1), 45–51 (1997).
  Medline CASGoogle Scholar
• 29. Bergmann O, Zdunek S, Felker A et al. Dynamics of cell generation and turnover in the human heart. Cell 161(7), 1566–1575 (2015).
  Medline CASGoogle Scholar
• 30. Meckert PC, Rivello HG, Vigliano C et al. Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction. Cardiovasc. Res. 67(1), 116–123 (2005).
  Medline CASGoogle Scholar
• 31. Mollova M, Bersell K, Walsh S et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc. Natl Acad. Sci. USA 110(4), 1446–1451 (2013).
  Medline CASGoogle Scholar
• 32. Miyaoka Y, Ebato K, Kato H et al. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr. Biol. 22(13), 1166–1175 (2012).
  Medline CASGoogle Scholar
• 33. Chen J, Huang Z-P, Seok HY et al. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circ. Res. 112(12), 1557–1566 (2013).
  Medline CASGoogle Scholar
• 34. Porrello ER, Mahmoud AI, Simpson E et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl Acad. Sci. USA 110(1), 187–192 (2013). • This study investigates the important role of the miR-15 family in mice cardiac regeneration and its potential therapeutic use following cardiac injury.
  Medline CASGoogle Scholar
• 35. Porrello ER, Johnson BA, Aurora AB et al. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ. Res. 109(6), 670–679 (2011).
  Medline CASGoogle Scholar
• 36. Yin VP, Lepilina A, Smith A, Poss KD. Regulation of zebrafish heart regeneration by miR-133. Dev. Biol. 365(2), 319–327 (2012).
  Medline CASGoogle Scholar
• 37. Diez-Cuñado M, Wei K, Bushway PJ et al. MiRNAs that induce human cardiomyocyte proliferation converge on the Hippo pathway. Cell Rep. 23(7), 2168–2174 (2018).
  Medline CASGoogle Scholar
• 38. Jackson T, Allard MF, Sreenan CM et al. The c-myc proto-oncogene regulates cardiac development in transgenic mice. Mol. Cell. Biol. 10(7), 3709–3716 (1990).
  Medline CASGoogle Scholar
• 39. Ahuja P, Zhao P, Angelis E et al. Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice. J. Clin. Invest. 120(5), 1494–1505 (2010).
  Medline CASGoogle Scholar
• 40. Wang Y, Li Y, Feng J et al. Mydgf promotes cardiomyocyte proliferation and neonatal heart regeneration. Theranostics 10(20), 9100–9112 (2020).
  Medline CASGoogle Scholar
• 41. Kisby T, Lázaro I, Fisch S et al. Adenoviral mediated delivery of OSKM factors induces partial reprogramming of mouse cardiac cells in vivo. Adv. Ther. 4(2), 2000141 (2021).
  CASGoogle Scholar
• 42. Bywater MJ, Burkhart DL, Straube J et al. Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity. Nat. Commun. 11(1), 1827 (2020). • This study explores c-Myc-induced cardiac regeneration and proposes an innovative way of enhancing it by manipulating P-TEFβ levels in mice.
  Medline CASGoogle Scholar
• 43. Sano M, Abdellatif M, Oh H et al. Activation and function of cyclin T–Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat. Med. 8(11), 1310–1317 (2002).
  Medline CASGoogle Scholar
• 44. Miklas JW, Levy S, Hofsteen P et al. Amino acid primed mTOR activity is essential for heart regeneration. iScience 25(1), 103574 (2022).
  Medline CASGoogle Scholar
• 45. Dicks S, Jürgensen L, Leuschner F et al. Cardiac regeneration and tumor growth-what do they have in common? Front. Genet. 11, 586658 (2020).
  Medline CASGoogle Scholar
• 46. Chen Y, Lüttmann FF, Schoger E et al. Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice. Science.373(6562), 1537–1540 (2021).
  Medline CASGoogle Scholar
• 47. Aharonov A, Shakked A, Umansky KB et al. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat. Cell Biol. 22(11), 1346–1356 (2020).
  Medline CASGoogle Scholar
• 48. Plouffe SW, Lin KC, Moore JL 3rd et al. The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J. Biol. Chem. 293(28), 11230–11240 (2018).
  Medline CASGoogle Scholar
• 49. Xiao Y, Dong J. The Hippo signaling pathway in cancer: a cell cycle perspective. Cancers 13(24), 6214(2021).
  Medline CASGoogle Scholar
• 50. Xin M, Kim Y, Sutherland LB et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110(34), 13839–13844 (2013).
  Medline CASGoogle Scholar
• 51. Heallen T, Morikawa Y, Leach J et al. Hippo signaling impedes adult heart regeneration. Development 140(23), 4683–4690 (2013).
  Medline CASGoogle Scholar
• 52. Von Gise A, Lin Z, Schlegelmilch K et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc. Natl Acad. Sci. USA 109(7), 2394–2399 (2012).
  Medline CASGoogle Scholar
• 53. Nishimoto M, Uranishi K, Asaka MN et al. Transformation of normal cells by aberrant activation of YAP via cMyc with TEAD. Sci. Rep. 9(1), 10933 (2019).
  MedlineGoogle Scholar
• 54. Flinn MA, Jeffery BE, O’Meara CC, Link BA. Yap is required for scar formation but not myocyte proliferation during heart regeneration in zebrafish. Cardiovasc. Res. 115(3), 570–577 (2019).
  Medline CASGoogle Scholar
• 55. Bo B, Li S, Zhou K, Wei J. The regulatory role of oxygen metabolism in exercise-induced cardiomyocyte regeneration. Front. Cell Dev. Biol. 9, 664527 (2021).
  MedlineGoogle Scholar
• 56. Fukuda R, Marín-Juez R, El-Sammak H et al. Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish. EMBO Rep. 21(8), e49752 (2020).
  Medline CASGoogle Scholar
• 57. Lopaschuk GD, Karwi QG, Tian R et al. Cardiac energy metabolism in heart failure. Circ. Res. 128(10), 1487–1513 (2021).
  Medline CASGoogle Scholar
• 58. Elhelaly WM, Lam NT, Hamza M et al. Redox regulation of heart regeneration: an evolutionary tradeoff. Front. Cell. Dev. Biol 4, 137 (2016).
  MedlineGoogle Scholar
• 59. Puente BN, Kimura W, Muralidhar SA et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157(3), 565–579 (2014).
  Medline CASGoogle Scholar
• 60. Bai C-G, Liu X-H, Liu W-Q, Ma D-L. Regional expression of the hypoxia-inducible factor (HIF) system and association with cardiomyocyte cell cycle re-entry after myocardial infarction in rats. Heart Vessels 23(3), 193–200 (2008).
  MedlineGoogle Scholar
• 61. Moslehi J, Minamishima YA, Shi J et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation 122(10), 1004–1016 (2010).
  Medline CASGoogle Scholar
• 62. Gauron C, Rampon C, Bouzaffour M et al. Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed. Sci. Rep. 3, 2084 (2013).
  Medline CASGoogle Scholar
• 63. Han P, Zhou X-H, Chang N et al. Hydrogen peroxide primes heart regeneration with a derepression mechanism. Cell Res. 24(9), 1091–1107 (2014). • This study provides evidence for the role of reactive oxygen species in cardiac repair in zebrafish and identifies downstream molecules such as PTPs, which may be potential therapeutic targets for cardiac regeneration.
  Medline CASGoogle Scholar
• 64. Smith AM, Maguire-Nguyen KK, Rando TA et al. The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues. NPJ Regen. Med. 2, 4 (2017).
  MedlineGoogle Scholar
• 65. Kimura W, Xiao F, Canseco DC et al. Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature 523(7559), 226–230 (2015).
  Medline CASGoogle Scholar
• 66. Faeh D, Moser A, Panczak R et al. Independent at heart: persistent association of altitude with ischaemic heart disease mortality after consideration of climate, topography and built environment. J. Epidemiol. Community Health 70(8), 798–806 (2016).
  MedlineGoogle Scholar
• 67. Ye L, Qiu L, Feng B et al. Role of blood oxygen saturation during post-natal human cardiomyocyte cell cycle activities. JACC Basic Transl. Sci. 5(5), 447–460 (2020).
  MedlineGoogle Scholar
• 68. Francis R, Chong J, Ramlall M et al. Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy. Basic Res. Cardiol. 116(1), 59 (2021).
  Medline CASGoogle Scholar
• 69. Bae J, Paltzer WG, Mahmoud AI. The role of metabolism in heart failure and regeneration. Front. Cardiovasc. Med.8, 702920 (2021)
  Medline CASGoogle Scholar
• 70. Tan J, Yang M, Wang H et al. Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch. Cell Rep. 38(10), 110468 (2022).
  Medline CASGoogle Scholar
• 71. Ali RL, Hakim JB, Boyle PM et al. Arrhythmogenic propensity of the fibrotic substrate after atrial fibrillation ablation: a longitudinal study using magnetic resonance imaging-based atrial models. Cardiovasc. Res. 115(12), 1757 (2019).
  Medline CASGoogle Scholar
• 72. Chen Z-T, Gao Q-Y, Wu M-X et al. Glycolysis inhibition alleviates cardiac fibrosis after myocardial infarction by suppressing cardiac fibroblast activation. Front. Cardiovasc. Med. 8, 701745 (2021).
  Medline CASGoogle Scholar
• 73. White IA, Gordon J, Balkan W, Hare JM. Sympathetic reinnervation is required for mammalian cardiac regeneration. Circ. Res. 117(12), 990–994 (2015).
  Medline CASGoogle Scholar
• 74. Rodriguez-Pallares J, Parga JA, Muñoz A et al. Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. J. Neurochem. 103(1), 145–156 (2007).
  Medline CASGoogle Scholar
• 75. Del Campo CV, Liaw NY, Gunadasa-Rohling M et al. Regenerative potential of epicardium-derived extracellular vesicles mediated by conserved miRNA transfer. Cardiovasc. Res. 118(2), 597–611 (2022).
  MedlineGoogle Scholar
• 76. Mahmoud AI, O’Meara CC, Gemberling M et al. Nerves regulate cardiomyocyte proliferation and heart regeneration. Dev. Cell 34(4), 387–399 (2015).
  Medline CASGoogle Scholar
• 77. Dae MW, Herre JM, O’Connell JW et al. Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction. J. Am. Coll. Cardiol. 17(6), 1416–1423 (1991).
  Medline CASGoogle Scholar
• 78. Lepilina A, Coon AN, Kikuchi K et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127(3), 607–619 (2006).
  Medline CASGoogle Scholar
• 79. Huang Y, Harrison MR, Osorio A et al. Igf signaling is required for cardiomyocyte proliferation during zebrafish heart development and regeneration. PLOS ONE.8(6), e67266 (2013).
  Medline CASGoogle Scholar
• 80. Kikuchi K, Holdway JE, Werdich AA et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464(7288), 601–605 (2010).
  Medline CASGoogle Scholar
• 81. Zhao L, Borikova AL, Ben-Yair R et al. Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration. Proc. Natl Acad. Sci. USA 111(4), 1403–1408 (2014).
  Medline CASGoogle Scholar
• 82. D’Uva G, Aharonov A, Lauriola M et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17(5), 627–638 (2015).
  MedlineGoogle Scholar
• 83. Honkoop H, De Bakker DE, Aharonov A et al. Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart. Elife 8, e50163 (2019).
  MedlineGoogle Scholar
• 84. Gemberling M, Karra R, Dickson AL, Poss KD. Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. Elife 4, e05871 (2015).
  MedlineGoogle Scholar
• 85. Polizzotti BD, Ganapathy B, Walsh S et al. Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window. Sci. Transl. Med. 7(281), 281ra45 (2015).
  MedlineGoogle Scholar
• 86. Ma H, Yin C, Zhang Y et al. ErbB2 is required for cardiomyocyte proliferation in murine neonatal hearts. Gene 592(2), 325–330 (2016).
  Medline CASGoogle Scholar
• 87. Takahashi T, Ishida K, Itoh K et al. IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model. Gene Ther. 10(8), 612–620 (2003).
  Medline CASGoogle Scholar
• 88. Ali SR, Elhelaly W, Nguyen NUN et al. Angiocrine IGFBP3 spatially coordinates IGF signaling during neonatal cardiac regeneration. bioRxiv 460522(2021).
  Google Scholar
• 89. Sallin P, Jaźwińska A. Acute stress is detrimental to heart regeneration in zebrafish. Open Biol. 6(3), 160012(2016).
  MedlineGoogle Scholar
• 90. Bassat E, Mutlak YE, Genzelinakh A et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547(7662), 179–184 (2017).
  Medline CASGoogle Scholar
• 91. Garcia-Puig A, Mosquera JL, Jiménez-Delgado S et al. Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration. Mol. Cell. Proteomics 18(9), 1745–1755 (2019). • This study explores the composition of extracellular matrix (ECM) in zebrafish and demonstrates that there is a sharp increase in specific ECM proteins following amputation. It highlights the differences in these ECM protein levels before and after resection and outlines their individual roles in cardiac regeneration.
  Medline CASGoogle Scholar
• 92. Notari M, Ventura-Rubio A, Bedford-Guaus SJ et al. The local microenvironment limits the regenerative potential of the mouse neonatal heart. Sci. Adv. 4(5), eaao5553 (2018). • The study shows that the composition of ECM in zebrafish undergoes an abundance of changes following amputation and highlights the influence of ECM handling on cardiac regeneration. The authors also highlight crucial changes in ECM stiffness during regeneration.
  MedlineGoogle Scholar
• 93. Yahalom-Ronen Y, Rajchman D, Sarig R et al. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. Elife.4, e07455 (2015).
  MedlineGoogle Scholar
• 94. Chen WCW, Wang Z, Missinato MA et al. Decellularized zebrafish cardiac extracellular matrix induces mammalian heart regeneration. Sci. Adv. 2(11), e1600844 (2016).
  MedlineGoogle Scholar
• 95. Yutzey KE. Regenerative biology: Neuregulin 1 makes heart muscle. Nature 520(7548), 445–446 (2015).
  Medline CASGoogle Scholar
• 96. Pfefferli C, Jaźwińska A. The careg element reveals a common regulation of regeneration in the zebrafish myocardium and fin. Nat. Commun. 8, 15151 (2017).
  MedlineGoogle Scholar
• 97. Chablais F, Jazwinska A. The regenerative capacity of the zebrafish heart is dependent on TGFβ signaling. Development 139(11), 1921–1930 (2012).
  Medline CASGoogle Scholar
• 98. George EL, Baldwin HS, Hynes RO. Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood 90(8), 3073–3081 (1997).
  Medline CASGoogle Scholar
• 99. Trinh LA, Stainier DYR. Fibronectin regulates epithelial organization during myocardial migration in zebrafish. Dev. Cell 6(3), 371–382 (2004).
  Medline CASGoogle Scholar
• 100. Jaźwińska A, Sallin P. Regeneration versus scarring in vertebrate appendages and heart. J. Pathol. 238(2), 233–246 (2016).
  MedlineGoogle Scholar
• 101. Kühn B, del Monte F, Hajjar RJ et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat. Med. 13(8), 962–969 (2007).
  Medline CASGoogle Scholar
• 102. Baehr A, Umansky KB, Bassat E et al. Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs. Circulation 142(9), 868–881 (2020).
  Medline CASGoogle Scholar
• 103. Chakraborty S, Njah K, Pobbati AV et al. Agrin as a mechanotransduction signal regulating YAP through the Hippo pathway. Cell Rep. 18(10), 2464–2479 (2017).
  Medline CASGoogle Scholar
• 104. Han C, Nie Y, Lian H et al. Acute inflammation stimulates a regenerative response in the neonatal mouse heart. Cell Res. 25(10), 1137–1151 (2015).
  Medline CASGoogle Scholar
• 105. Aurora AB, Porrello ER, Tan W et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124(3), 1382–1392 (2014). • This study highlights the importance of the role of the immune system in regulating cardiac regeneration and specifically the differential role of macrophages in regeneration of myocardium of neonatal mice. It shows that macrophage depletion removes the ability of neonatal mice to regenerate their myocardium.
  Medline CASGoogle Scholar
• 106. Glaros T, Larsen M, Li L. Macrophages and fibroblasts during inflammation, tissue damage and organ injury. Front. Biosci. 14(10), 3988–3993 (2009).
  CASGoogle Scholar
• 107. Schulz C, Gomez Perdiguero E, Chorro L et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077), 86–90 (2012).
  Medline CASGoogle Scholar
• 108. Hashimoto D, Chow A, Noizat C et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38(4), 792–804 (2013).
  Medline CASGoogle Scholar
• 109. Yona S, Kim K-W, Wolf Y et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1), 79–91 (2013).
  Medline CASGoogle Scholar
• 110. Ginhoux F, Greter M, Leboeuf M et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005), 841–845 (2010).
  Medline CASGoogle Scholar
• 111. Hoeffel G, Wang Y, Greter M et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209(6), 1167–1181 (2012).
  Medline CASGoogle Scholar
• 112. Lavine KJ, Epelman S, Uchida K et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl. Acad. Sci. U. S. A. 111(45), 16029–16034 (2014).
  Medline CASGoogle Scholar
• 113. Epelman S, Lavine KJ, Beaudin AE et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40(1), 91–104 (2014).
  Medline CASGoogle Scholar
• 114. Bajpai G, Bredemeyer A, Li W et al. Tissue resident CCR2- and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ. Res. 124(2), 263–278 (2019).
  Medline CASGoogle Scholar
• 115. Roberts R, DeMello V, Sobel BE. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 53(Suppl. 3), I204–6 (1976).
  Medline CASGoogle Scholar
• 116. Bevan L, Lim ZW, Venkatesh B et al. Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish. Cardiovasc. Res. 116(7), 1357–1371 (2020).
  Medline CASGoogle Scholar
• 117. Kirchmaier S, Naruse K, Wittbrodt J, Loosli F. The genomic and genetic toolbox of the teleost medaka (Oryzias latipes). Genetics 199(4), 905–918 (2015).
  Medline CASGoogle Scholar
• 118. Ito K, Morioka M, Kimura S et al. Differential reparative phenotypes between zebrafish and medaka after cardiac injury. Dev. Dyn. 243(9), 1106–1115 (2014).
  Medline CASGoogle Scholar
• 119. Lai S-L, Marín-Juez R, Moura PL et al. Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration. Elife.6, 6 (2017).
  Google Scholar
• 120. Potts HG, Stockdale WT, Mommersteeg MTM. Unlocking the secrets of the regenerating fish heart: comparing regenerative models to shed light on successful regeneration. J. Cardiovasc. Dev. Dis. 8(1), 4 (2021).
  MedlineGoogle Scholar
• 121. Wodsedalek DJ, Paddock SJ, Wan TC et al. IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration. Am. J. Physiol. Heart Circ. Physiol. 316(1), H24–H34 (2019).
  Medline CASGoogle Scholar
• 122. Hui SP, Sheng DZ, Sugimoto K et al. Zebrafish regulatory T cells mediate organ-specific regenerative programs. Dev. Cell 43(6), 659–672.e5 (2017).
  Medline CASGoogle Scholar
• 123. Miller DM, Thomas SD, Islam A et al. c-Myc and cancer metabolism. Clin. Cancer Res. 18(20), 5546–5553 (2012).
  Medline CASGoogle Scholar
• 124. Tanner JJ, Parsons ZD, Cummings AH et al. Redox regulation of protein tyrosine phosphatases: structural and chemical aspects. Antioxid. Redox Signal. 15(1), 77–97 (2011).
  Medline CASGoogle Scholar
• 125. Adler CP, Friedburg H. Myocardial DNA content, ploidy level and cell number in geriatric hearts: post-mortem examinations of human myocardium in old age. J. Mol. Cell. Cardiol. 18(1), 39–53 (1986).
  Medline CASGoogle Scholar