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

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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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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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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