Review Article | Published:

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

Nature Reviews Cardiologyvolume 15pages672684 (2018) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 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).

  5. 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).

  6. 6.

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

  7. 7.

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

  8. 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).

  9. 9.

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

  10. 10.

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

  11. 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).

  12. 12.

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

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 19.

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

  20. 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).

  21. 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).

  22. 22.

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

  23. 23.

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

  24. 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).

  25. 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).

  26. 26.

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

  27. 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).

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

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

  33. 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).

  34. 34.

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

  35. 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).

  36. 36.

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

  37. 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).

  38. 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).

  39. 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).

  40. 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).

  41. 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).

  42. 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).

  43. 43.

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

  44. 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).

  45. 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).

  46. 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).

  47. 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).

  48. 48.

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

  49. 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).

  50. 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).

  51. 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).

  52. 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).

  53. 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).

  54. 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).

  55. 55.

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

  56. 56.

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

  57. 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).

  58. 58.

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

  59. 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).

  60. 60.

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

  61. 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).

  62. 62.

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

  63. 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).

  64. 64.

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

  65. 65.

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

  66. 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).

  67. 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).

  68. 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).

  69. 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).

  70. 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).

  71. 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).

  72. 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).

  73. 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).

  74. 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).

  75. 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).

  76. 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).

  77. 77.

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

  78. 78.

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

  79. 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).

  80. 80.

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

  81. 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).

  82. 82.

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

  83. 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).

  84. 84.

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

  85. 85.

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

  86. 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).

  87. 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).

  88. 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).

  89. 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).

  90. 90.

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

  91. 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).

  92. 92.

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

  93. 93.

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

  94. 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).

  95. 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).

  96. 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).

  97. 97.

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

  98. 98.

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

  99. 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).

  100. 100.

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

  101. 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).

  102. 102.

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

  103. 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).

  104. 104.

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

  105. 105.

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

  106. 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).

  107. 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).

  108. 108.

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

  109. 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).

  110. 110.

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

  111. 111.

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

  112. 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).

  113. 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).

  114. 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).

  115. 115.

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

  116. 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).

  117. 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).

  118. 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).

  119. 119.

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

  120. 120.

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

  121. 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).

  122. 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).

  123. 123.

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

  124. 124.

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

  125. 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).

  126. 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).

  127. 127.

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

  128. 128.

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

  129. 129.

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

  130. 130.

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

  131. 131.

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

  132. 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).

  133. 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).

  134. 134.

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

  135. 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).

  136. 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).

  137. 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).

  138. 138.

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

  139. 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).

  140. 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).

  141. 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).

  142. 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).

  143. 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).

  144. 144.

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

  145. 145.

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

  146. 146.

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

  147. 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).

  148. 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).

  149. 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).

  150. 150.

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

  151. 151.

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

  152. 152.

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

  153. 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).

  154. 154.

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

  155. 155.

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

  156. 156.

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

  157. 157.

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

  158. 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).

  159. 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).

  160. 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).

  161. 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).

Download references

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.

Author information

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

Authors

  1. Search for Jun Wang in:

  2. Search for Shijie Liu in:

  3. Search for Todd Heallen in:

  4. Search for James F. Martin in:

Contributions

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.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Jun Wang or James F. Martin.

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.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41569-018-0063-3