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The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration

Nature Reviews Cardiology volume 15, pages 672–684 (2018)Cite this article

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Abstract

The Hippo–YAP (Yes-associated protein) pathway is an evolutionarily and functionally conserved regulator of organ size and growth with crucial roles in cell proliferation, apoptosis, and differentiation. This pathway has great potential for therapeutic manipulation in different disease states and to promote organ regeneration. In this Review, we summarize findings from the past decade revealing the function and regulation of the Hippo–YAP pathway in cardiac development, growth, homeostasis, disease, and regeneration. In particular, we highlight the roles of the Hippo–YAP pathway in endogenous heart muscle renewal, including the pivotal role of the Hippo–YAP pathway in regulating cardiomyocyte proliferation and differentiation, stress response, and mechanical signalling. The human heart lacks the capacity to self-repair; therefore, the loss of cardiomyocytes after injury such as myocardial infarction can result in heart failure and death. Despite substantial advances in the treatment of heart failure, an enormous unmet clinical need exists for alternative treatment options. Targeting the Hippo–YAP pathway has tremendous potential for developing therapeutic strategies for cardiac repair and regeneration for currently intractable cardiovascular diseases such as heart failure. The lessons learned from cardiac repair and regeneration studies will also bring new insights into the regeneration of other tissues with limited regenerative capacity.

Key points

  • The Hippo–YAP (Yes-associated protein) pathway is an evolutionarily conserved pathway that controls organ size.

  • Hippo signalling restrains cardiomyocyte proliferation during development to control cardiac size.

  • The Hippo–YAP pathway regulates the activity of growth pathways during prenatal and postnatal life and is important for cardiac homeostasis.

  • Hippo signalling inhibits adult cardiac regeneration.

  • The Hippo–YAP pathway regulates various events during cardiac regeneration, including cardiomyocyte proliferation and differentiation, injury resistance, stress response, and mechanical signals.

  • Manipulating the Hippo–YAP pathway is a potential therapeutic tool for treating cardiac injury.

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Fig. 1: Summary of Hippo signalling.
Fig. 2: Developmental regulation of heart size by the Hippo pathway.
Fig. 3: Hippo signalling in cardiac regeneration.
Fig. 4: Hippo signalling regulation in cardiac regeneration.

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References

  1. Edgar, B. A. From cell structure to transcription: Hippo forges a new path. Cell 124, 267–273 (2006).

    CAS  PubMed  Google Scholar 

  2. Varelas, X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 141, 1614–1626 (2014).

    CAS  PubMed  Google Scholar 

  3. Wang, J. & Martin, J. F. Hippo pathway: an emerging regulator of craniofacial and dental development. J. Dent. Res. 96, 1229–1237 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Xiao, Y., Leach, J., Wang, J. & Martin, J. F. Hippo/Yap signaling in cardiac development and regeneration. Curr. Treat. Options Cardiovasc. Med. 18, 38 (2016).

    PubMed  Google Scholar 

  5. Fu, V., Plouffe, S. W. & Guan, K. L. The Hippo pathway in organ development, homeostasis, and regeneration. Curr. Opin. Cell Biol. 49, 99–107 (2017).

    CAS  PubMed  Google Scholar 

  6. Ikeda, S. & Sadoshima, J. Regulation of myocardial cell growth and death by the Hippo pathway. Circ. J. 80, 1511–1519 (2016).

    CAS  PubMed  Google Scholar 

  7. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Benjamin, E. J. et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135, e146–e603 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. Heallen, T. et al. Hippo signaling impedes adult heart regeneration. Development 140, 4683–4690 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Leach, J. P. et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550, 260–264 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Lin, Z. et al. Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ. Res. 115, 354–363 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Xin, M. et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang, J. et al. TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPalpha function. Mol. Cell 51, 211–225 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, T. et al. Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. Hepatology 56, 2051–2059 (2012).

    CAS  PubMed  Google Scholar 

  15. Zagurovskaya, M. et al. EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells. Oncogene 28, 1121–1131 (2009).

    CAS  PubMed  Google Scholar 

  16. Nguyen, L. T. et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell 27, 797–808 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Komuro, A., Nagai, M., Navin, N. E. & Sudol, M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J. Biol. Chem. 278, 33334–33341 (2003).

    CAS  PubMed  Google Scholar 

  18. Zhang, W. et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci. Signal. 7, ra42 (2014).

    PubMed  PubMed Central  Google Scholar 

  19. Shao, D. et al. A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat. Commun. 5, 3315 (2014).

    PubMed  Google Scholar 

  20. Eisinger-Mathason, T. S. et al. Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis. Proc. Natl Acad. Sci. USA 112, E3402–E3411 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bendinelli, P. et al. Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer. Eur. J. Cancer 49, 2608–2618 (2013).

    CAS  PubMed  Google Scholar 

  22. Ma, B. et al. Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat. Cell Biol. 17, 95–103 (2015).

    CAS  PubMed  Google Scholar 

  23. Tariki, M. et al. The Yes-associated protein controls the cell density regulation of Hedgehog signaling. Oncogenesis 3, e112 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhi, X., Zhao, D., Zhou, Z., Liu, R. & Chen, C. YAP promotes breast cell proliferation and survival partially through stabilizing the KLF5 transcription factor. Am. J. Pathol. 180, 2452–2461 (2012).

    CAS  PubMed  Google Scholar 

  25. Gao, Y. et al. Curcumin promotes KLF5 proteasome degradation through downregulating YAP/TAZ in bladder cancer cells. Int. J. Mol. Sci. 15, 15173–15187 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Jeong, H. et al. TAZ as a novel enhancer of MyoD-mediated myogenic differentiation. FASEB J. 24, 3310–3320 (2010).

    CAS  PubMed  Google Scholar 

  27. Beyer, T. A. et al. Switch enhancers interpret TGF-beta and Hippo signaling to control cell fate in human embryonic stem cells. Cell Rep. 5, 1611–1624 (2013).

    CAS  PubMed  Google Scholar 

  28. Murakami, M. et al. Transcriptional activity of Pax3 is co-activated by TAZ. Biochem. Biophys. Res. Commun. 339, 533–539 (2006).

    CAS  PubMed  Google Scholar 

  29. Manderfield, L. J. et al. Pax3 and hippo signaling coordinate melanocyte gene expression in neural crest. Cell Rep. 9, 1885–1895 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tao, G. et al. Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534, 119–123 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).

    CAS  PubMed  Google Scholar 

  32. Chatterjee, A., Sen, T., Chang, X. & Sidransky, D. Yes-associated protein 1 regulates the stability of DeltaNp63alpha. Cell Cycle 9, 162–167 (2010).

    CAS  PubMed  Google Scholar 

  33. Valencia-Sama, I. et al. Hippo component TAZ functions as a co-repressor and negatively regulates DeltaNp63 transcription through TEA domain (TEAD) transcription factor. J. Biol. Chem. 290, 16906–16917 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Strano, S. et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276, 15164–15173 (2001).

    CAS  PubMed  Google Scholar 

  35. Basu, S., Totty, N. F., Irwin, M. S., Sudol, M. & Downward, J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol. Cell 11, 11–23 (2003).

    CAS  PubMed  Google Scholar 

  36. Lapi, E. et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol. Cell 32, 803–814 (2008).

    CAS  PubMed  Google Scholar 

  37. Yagi, R., Chen, L. F., Shigesada, K., Murakami, Y. & Ito, Y. A. WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18, 2551–2562 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Cui, C. B., Cooper, L. F., Yang, X., Karsenty, G. & Aukhil, I. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol. Cell. Biol. 23, 1004–1013 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol. Cell 29, 350–361 (2008).

    CAS  PubMed  Google Scholar 

  40. Ferrigno, O. et al. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21, 4879–4884 (2002).

    CAS  PubMed  Google Scholar 

  41. Varelas, X. et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol. 10, 837–848 (2008).

    CAS  PubMed  Google Scholar 

  42. Wrighton, K. H., Dai, F. & Feng, X. H. A new kid on the TGFbeta block: TAZ controls Smad nucleocytoplasmic shuttling. Dev. Cell 15, 8–10 (2008).

    CAS  PubMed  Google Scholar 

  43. Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139, 757–769 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev. Cell 19, 831–844 (2010).

    CAS  PubMed  Google Scholar 

  45. Fujii, M. et al. TGF-beta synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J. Exp. Med. 209, 479–494 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Narimatsu, M., Samavarchi-Tehrani, P., Varelas, X. & Wrana, J. L. Distinct polarity cues direct Taz/Yap and TGFbeta receptor localization to differentially control TGFbeta-induced Smad signaling. Dev. Cell 32, 652–656 (2015).

    CAS  PubMed  Google Scholar 

  47. Murakami, M., Nakagawa, M., Olson, E. N. & Nakagawa, O. A. WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc. Natl Acad. Sci. USA 102, 18034–18039 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Rosenbluh, J. et al. beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151, 1457–1473 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Park, K. S. et al. TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. J. Biol. Chem. 279, 17384–17390 (2004).

    CAS  PubMed  Google Scholar 

  50. Ragni, C. V. et al. Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth. Nat. Commun. 8, 14582 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Jiao, S. et al. VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nat. Commun. 8, 14058 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jiao, S. et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25, 166–180 (2014).

    CAS  PubMed  Google Scholar 

  53. Zhang, W. et al. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res. 24, 331–343 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Matsuda, T. et al. NF2 activates hippo signaling and promotes ischemia/reperfusion injury in the heart. Circ. Res. 119, 596–606 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Brennan, J. et al. Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411, 965–969 (2001).

    CAS  PubMed  Google Scholar 

  57. Lescroart, F. et al. Early lineage restriction in temporally distinct populations of Mesp1 progenitors during mammalian heart development. Nat. Cell Biol. 16, 829–840 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Später, D., Hansson, E. M., Zangi, L. & Chien, K. R. How to make a cardiomyocyte. Development 141, 4418–4431 (2014).

    PubMed  Google Scholar 

  59. Yue, Q., Wagstaff, L., Yang, X., Weijer, C. & Munsterberg, A. Wnt3a-mediated chemorepulsion controls movement patterns of cardiac progenitors and requires RhoA function. Development 135, 1029–1037 (2008).

    CAS  PubMed  Google Scholar 

  60. Lopez-Sanchez, C. & Garcia-Martinez, V. Molecular determinants of cardiac specification. Cardiovasc. Res. 91, 185–195 (2011).

    CAS  PubMed  Google Scholar 

  61. Naito, A. T. et al. Developmental stage-specific biphasic roles of Wnt/β-catenin signaling in cardiomyogenesis and hematopoiesis. Proc. Natl Acad. Sci. USA 103, 19812–19817 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Galdos, F. X. et al. Cardiac regeneration: lessons from development. Circ. Res. 120, 941–959 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ai, D. et al. Canonical Wnt signaling functions in second heart field to promote right ventricular growth. Proc. Natl Acad. Sci. USA 104, 9319–9324 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Olson, E. N. Gene regulatory networks in the evolution and development of the heart. Science 313, 1922–1927 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Meilhac, S. M. & Buckingham, M. E. The deployment of cell lineages that form the mammalian heart. Nat. Rev. Cardiol. (in the press).

  66. Vincent, S. D. & Buckingham, M. E. How to make a heart: the origin and regulation of cardiac progenitor cells. Curr. Top. Dev. Biol. 90, 1–41 (2010).

    PubMed  Google Scholar 

  67. von Gise, A. et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc. Natl Acad. Sci. USA 109, 2394–2399 (2012).

    Google Scholar 

  68. Xin, M. et al. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci. Signal. 4, ra70 (2011).

    PubMed  PubMed Central  Google Scholar 

  69. Moses, K. A., DeMayo, F., Braun, R. M., Reecy, J. L. & Schwartz, R. J. Embryonic expression of an Nkx2-5/Cre gene using ROSA26 reporter mice. Genesis 31, 176–180 (2001).

    CAS  PubMed  Google Scholar 

  70. Chen, Z., Friedrich, G. A. & Soriano, P. Transcriptional enhancer factor 1 disruption by a retroviral gene trap leads to heart defects and embryonic lethality in mice. Genes Dev. 8, 2293–2301 (1994).

    CAS  PubMed  Google Scholar 

  71. Tsika, R. W. et al. TEAD-1 overexpression in the mouse heart promotes an age-dependent heart dysfunction. J. Biol. Chem. 285, 13721–13735 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Xiao, Y. et al. Hippo signaling plays an essential role in cell state transitions during cardiac fibroblast development. Dev. Cell 45, 153–169.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Katz, T. C. et al. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev. Cell 22, 639–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Acharya, A. et al. The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 139, 2139–2149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wessels, A. & Perez-Pomares, J. M. The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 276, 43–57 (2004).

    CAS  PubMed  Google Scholar 

  76. Singh, A. et al. Hippo signaling mediators Yap and Taz are required in the epicardium for coronary vasculature development. Cell Rep. 15, 1384–1393 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Varelas, X. et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev. Cell 18, 579–591 (2010).

    CAS  PubMed  Google Scholar 

  78. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Tumaneng, K. et al. YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via miR-29. Nat. Cell Biol. 14, 1322–1329 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ahuja, P., Sdek, P. & MacLellan, W. R. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol. Rev. 87, 521–544 (2007).

    CAS  PubMed  Google Scholar 

  81. Frey, N., Katus, H. A., Olson, E. N. & Hill, J. A. Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580–1589 (2004).

    PubMed  Google Scholar 

  82. Murphy, E. & Steenbergen, C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol. Rev. 88, 581–609 (2008).

    CAS  PubMed  Google Scholar 

  83. Del, Re,D. P. et al. Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. J. Biol. Chem. 288, 3977–3988 (2013).

    Google Scholar 

  84. Yang, Y. et al. miR-206 mediates YAP-induced cardiac hypertrophy and survival. Circ. Res. 117, 891–904 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, P. et al. The alteration of Hippo/YAP signaling in the development of hypertrophic cardiomyopathy. Basic Res. Cardiol. 109, 435 (2014).

    PubMed  Google Scholar 

  86. Yamamoto, S. et al. Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. J. Clin. Invest. 111, 1463–1474 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Odashima, M. et al. Inhibition of endogenous Mst1 prevents apoptosis and cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ. Res. 100, 1344–1352 (2007).

    CAS  PubMed  Google Scholar 

  88. Del, Re,D. P. et al. Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. J. Clin. Invest. 120, 3555–3567 (2010).

    Google Scholar 

  89. Oceandy, D. et al. Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy. Circulation 120, 607–616 (2009).

    CAS  PubMed  Google Scholar 

  90. Matsui, Y. et al. Lats2 is a negative regulator of myocyte size in the heart. Circ. Res. 103, 1309–1318 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen, S. N. et al. The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circ. Res. 114, 454–468 (2014).

    CAS  PubMed  Google Scholar 

  92. Oberpriller, J. O. & Oberpriller, J. C. Response of the adult newt ventricle to injury. J. Exp. Zool. 187, 249–253 (1974).

    CAS  PubMed  Google Scholar 

  93. Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

    CAS  PubMed  Google Scholar 

  94. Porrello, E. R. et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl Acad. Sci. USA 110, 187–192 (2013).

    CAS  PubMed  Google Scholar 

  95. Lloyd-Jones, D. et al. Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121, 948–954 (2010).

    PubMed  Google Scholar 

  96. Writing Group Members. et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121, e46–e215 (2010).

    Google Scholar 

  97. Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kikuchi, K. et al. Primary contribution to zebrafish heart regeneration by gata4( + ) cardiomyocytes. Nature 464, 601–605 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao, B., Lei, Q. Y. & Guan, K. L. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr. Opin. Cell Biol. 20, 638–646 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Agah, R. et al. Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J. Clin. Invest. 100, 169–179 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Li, J. et al. Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity. Circ. Res. 116, 70–79 (2015).

    CAS  PubMed  Google Scholar 

  103. Vite, A., Zhang, C., Yi, R., Emms, S. & Radice, G. L. Alpha-catenin-dependent cytoskeletal tension controls Yap activity in the heart. Development 145, dev149823 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. Lin, Z. et al. Acetylation of VGLL4 regulates Hippo-YAP signaling and postnatal cardiac growth. Dev. Cell 39, 466–479 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Girard, J., Ferre, P., Pegorier, J. P. & Duee, P. H. Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiol. Rev. 72, 507–562 (1992).

    CAS  PubMed  Google Scholar 

  107. Lopaschuk, G. D. & Jaswal, J. S. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J. Cardiovasc. Pharmacol. 56, 130–140 (2010).

    CAS  PubMed  Google Scholar 

  108. Sim, C. B. et al. Dynamic changes in the cardiac methylome during postnatal development. FASEB J. 29, 1329–1343 (2015).

    CAS  PubMed  Google Scholar 

  109. Mills, R. J. et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc. Natl Acad. Sci. USA 114, E8372–E8381 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Coggins, M. & Rosenzweig, A. The fire within: cardiac inflammatory signaling in health and disease. Circ. Res. 110, 116–125 (2012).

    CAS  PubMed  Google Scholar 

  111. Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. van Amerongen, M. J., Harmsen, M. C., van Rooijen, N., Petersen, A. H. & van Luyn, M. J. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am. J. Pathol. 170, 818–829 (2007).

    PubMed  PubMed Central  Google Scholar 

  113. Leblond, A. L. et al. Systemic and cardiac depletion of M2 macrophage through CSF-1R signaling inhibition alters cardiac function post myocardial infarction. PLoS ONE 10, e0137515 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Morimoto, H. et al. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. Circ. Res. 99, 891–899 (2006).

    CAS  PubMed  Google Scholar 

  115. Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Puente, B. N. et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157, 565–579 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Lehtinen, M. K. et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987–1001 (2006).

    CAS  PubMed  Google Scholar 

  118. Morikawa, Y. et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci. Signal. 8, ra41 (2015).

    PubMed  PubMed Central  Google Scholar 

  119. Maejima, Y. et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat. Med. 19, 1478–1488 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Huang, G. N. et al. C/EBP transcription factors mediate epicardial activation during heart development and injury. Science 338, 1599–1603 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. van Wijk, B., Gunst, Q. D., Moorman, A. F. & van den Hoff, M. J. Cardiac regeneration from activated epicardium. PLoS ONE 7, e44692 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. Wang, J., Karra, R., Dickson, A. L. & Poss, K. D. Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. Dev. Biol. 382, 427–435 (2013).

    CAS  PubMed  Google Scholar 

  123. Smart, N. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474, 640–644 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Ramjee, V. et al. Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J. Clin. Invest. 127, 899–911 (2017).

    PubMed  PubMed Central  Google Scholar 

  125. Cao, J. & Poss, K. The epicardium as a hub for heart regeneration. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-018-0046-4 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. Halder, G., Dupont, S. & Piccolo, S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012).

    CAS  PubMed  Google Scholar 

  127. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    CAS  PubMed  Google Scholar 

  128. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    CAS  PubMed  Google Scholar 

  129. Zhao, B. et al. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26, 54–68 (2012).

    PubMed  PubMed Central  Google Scholar 

  130. Sansores-Garcia, L. et al. Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J. 30, 2325–2335 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Yu, F. X. & Guan, K. L. The Hippo pathway: regulators and regulations. Genes Dev. 27, 355–371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Mosqueira, D. et al. Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. ACS Nano 8, 2033–2047 (2014).

    CAS  PubMed  Google Scholar 

  133. Yui, S. et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 35–49.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Morikawa, Y., Heallen, T., Leach, J., Xiao, Y. & Martin, J. F. Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547, 227–231 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Angst, B. D. et al. Dissociated spatial patterning of gap junctions and cell adhesion junctions during postnatal differentiation of ventricular myocardium. Circ. Res. 80, 88–94 (1997).

    CAS  PubMed  Google Scholar 

  137. Hirschy, A., Schatzmann, F., Ehler, E. & Perriard, J. C. Establishment of cardiac cytoarchitecture in the developing mouse heart. Dev. Biol. 289, 430–441 (2006).

    CAS  PubMed  Google Scholar 

  138. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP/TAZ at the roots of cancer. Cancer Cell 29, 783–803 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Wada, K., Itoga, K., Okano, T., Yonemura, S. & Sasaki, H. Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907–3914 (2011).

    CAS  PubMed  Google Scholar 

  140. Densham, R. M. et al. MST kinases monitor actin cytoskeletal integrity and signal via c-Jun N-terminal kinase stress-activated kinase to regulate p21Waf1/Cip1 stability. Mol. Cell. Biol. 29, 6380–6390 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Fernandez, B. G. et al. Actin-Capping protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 138, 2337–2346 (2011).

    CAS  PubMed  Google Scholar 

  142. Gagne, V. et al. Human angiomotin-like 1 associates with an angiomotin protein complex through its coiled-coil domain and induces the remodeling of the actin cytoskeleton. Cell. Motil. Cytoskeleton 66, 754–768 (2009).

    CAS  PubMed  Google Scholar 

  143. McCartney, B. M., Kulikauskas, R. M., LaJeunesse, D. R. & Fehon, R. G. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation. Development 127, 1315–1324 (2000).

    CAS  PubMed  Google Scholar 

  144. Wang, J. & Martin, J. F. Macro advances in microRNAs and myocardial regeneration. Curr. Opin. Cardiol. 29, 207–213 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. Tian, Y. et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci. Transl Med. 7, 279ra38 (2015).

    PubMed  PubMed Central  Google Scholar 

  146. Zhao, B. et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22, 1962–1971 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhang, H. et al. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J. Biol. Chem. 284, 13355–13362 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhao, B., Kim, J., Ye, X., Lai, Z. C. & Guan, K. L. Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein. Cancer Res. 69, 1089–1098 (2009).

    CAS  PubMed  Google Scholar 

  149. Lin, Z. et al. Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ. Res. 116, 35–45 (2015).

    CAS  PubMed  Google Scholar 

  150. Schlegelmilch, K. et al. Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Moroishi, T. et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 29, 1271–1284 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Barry, E. R. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013).

    PubMed  Google Scholar 

  153. Imajo, M., Miyatake, K., Iimura, A., Miyamoto, A. & Nishida, E. A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J. 31, 1109–1122 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Azzolin, L. et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

    CAS  PubMed  Google Scholar 

  155. Azzolin, L. et al. Role of TAZ as mediator of Wnt signaling. Cell 151, 1443–1456 (2012).

    CAS  PubMed  Google Scholar 

  156. Ozhan, G. & Weidinger, G. Wnt/beta-catenin signaling in heart regeneration. Cell Regen. (Lond.) 4, 3 (2015).

    Google Scholar 

  157. D’Uva, G. et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17, 627–638 (2015).

    PubMed  Google Scholar 

  158. Zelarayan, L. C. et al. Beta-catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation. Proc. Natl Acad. Sci. USA 105, 19762–19767 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Wo, D. et al. Opposing roles of Wnt inhibitors IGFBP-4 and Dkk1 in cardiac ischemia by differential targeting of LRP5/6 and beta-catenin. Circulation 134, 1991–2007 (2016).

    CAS  PubMed  Google Scholar 

  160. Estaras, C., Hsu, H. T., Huang, L. & Jones, K. A. YAP repression of the WNT3 gene controls hESC differentiation along the cardiac mesoderm lineage. Genes Dev. 31, 2250–2263 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Gregorieff, A., Liu, Y., Inanlou, M. R., Khomchuk, Y. & Wrana, J. L. Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer. Nature 526, 715–718 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to researchers whose work is not cited here because of space constraints. The authors thank the following funding sources: the AHA National Center Scientist Development Grant (14SDG19840000 to J.W.; 16SDG26460001 to T.H.) and Postdoctoral Fellowship (18POST34060186 to S.L.), the NIH (DE026561 and DE025873 to J.W.; DE 023177, HL 127717, HL 130804, and HL 118761 to J.F.M.), the DOD (W81XWH-17-1-0418 to J.F.M.) and the Vivian L. Smith Foundation (to J.F.M.). J.F.M. received support from the LeDucq Foundation’s Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01) and the MacDonald Research Fund Award 16RDM001. N. Stancel (Texas Heart Institute, USA) provided editorial support.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA

    Jun Wang & James F. Martin

  2. Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, TX, USA

    Shijie Liu, Todd Heallen & James F. Martin

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  1. Jun Wang
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J.W. and J.F.M. provided substantial contribution to the discussion of the content. All the authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Jun Wang or James F. Martin.

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Glossary

Morphogen

Signalling molecule that forms a concentration gradient to guide and determine tissue pattern formation during morphogenesis. Cell fates and responses depend on morphogen concentration, thus morphogens are required for differentiation and position determination of the various cell types in a tissue and have a crucial role in development.

Epiblast

Group of cells (also known as primitive ectoderm) that form the outermost layer above the hypoblast of the embryo. The epiblast is derived from the inner cell mass and gives rise to the three primary germ layers (ectoderm, mesoderm, and endoderm), the extra-embryonic mesoderm, the amniotic ectoderm, and the allantois.

Cardiac crescent

During mammal heart formation, before the heart tube forms, heart progenitor cells in the cranio-lateral mesoderm fuse at the midline to form a bilateral crescent-shape structure known as the cardiac crescent.

Pharyngeal mesoderm

The mesodermal cell population located in the head region of the embryo; contributes to the pharyngeal arch cores and the second heart field during embryonic development.

Gene trapping

A high-throughput mutagenesis approach for introducing insertional mutations thoughout the genome.

Intercalated discs

Unique junctions that connect cardiomyocytes together and define their borders, which is a special feature of cardiac muscle and is required for cardiac cell–cell communication and coordination of muscle contraction.

Glycolysis

Metabolic pathway that breaks down glucose to pyruvate and releases energy to form ATP and NADH for cellular metabolism.

Fatty acid oxidation

A multistep catabolic process (also known as β-oxidation) in which fatty acids are broken down to generate acetyl-CoA, which then enters the citric acid cycle that produces energy for cellular metabolism.

Myofibroblasts

Cells that have a phenotype between fibroblasts and smooth muscle cells, which is usually defined by expression of α-smooth muscle actin (also known as ACTA2); myofibroblasts are crucial in wound repair.

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Wang, J., Liu, S., Heallen, T. et al. The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat Rev Cardiol 15, 672–684 (2018). https://doi.org/10.1038/s41569-018-0063-3

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