Hippo signaling impedes adult heart regeneration
01 Dec 2013-Development (Oxford University Press for The Company of Biologists Limited)-Vol. 140, Iss: 23, pp 4683-4690
TL;DR: The findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration and Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease.
Abstract: Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes. Here, we investigated Hippo signaling in adult cardiomyocyte renewal and regeneration. We found that unstressed Hippo-deficient adult mouse cardiomyocytes re-enter the cell cycle and undergo cytokinesis. Moreover, Hippo deficiency enhances cardiomyocyte regeneration with functional recovery after adult myocardial infarction as well as after postnatal day eight (P8) cardiac apex resection and P8 myocardial infarction. In damaged hearts, Hippo mutant cardiomyocytes also have elevated proliferation. Our findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration. Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease.
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TL;DR: The Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status.
1,571 citations
Cites background from "Hippo signaling impedes adult heart..."
...In contrast, cardiac-specific deletion of Yap impedes regeneration of the neonatal heart (Heallen et al., 2013; Lin et al., 2014; Xin et al., 2013)....
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TL;DR: YAP/TAZ appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context, and are appealing therapeutic targets in cancer and regenerative medicine.
Abstract: The transcriptional regulators YAP and TAZ are the focus of intense interest given their remarkable biological properties in development, tissue homeostasis and cancer. YAP and TAZ activity is key ...
1,250 citations
Cites background from "Hippo signaling impedes adult heart..."
...Similarly, deletion of Salvador/WW45 and LATS1/2 in adult cardiomyocytes enabled their proliferation in postnatal life, facilitating heart regeneration upon infarction or partial surgical resection (83)....
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TL;DR: The regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators are reviewed.
Abstract: The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.
780 citations
TL;DR: An overview of regulatory mechanisms and important developmental processes controlled by TAZ and YAP is provided and it is outlined that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors.
Abstract: Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.
539 citations
Cites background from "Hippo signaling impedes adult heart..."
...Additionally, conditional deletion of Sav1 or Lats1/2 enhances cardiomyocyte regeneration afteradultmyocardial infarction (Heallen et al., 2013)....
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TL;DR: The role of the NRG1 co-receptor ERBB2 in cardiac regeneration is explored using loss- and gain-of-function genetic tools, and it is shown that ER BB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.
Abstract: The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/β-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.
512 citations
References
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TL;DR: The mT/mG mouse as mentioned in this paper is a double-fluorescent Cre reporter mouse that expresses membrane-targeted tandem dimer tomato (mT) prior to Cre-mediated excision and membranetargeted green fluorescent protein (mG) after excision.
Abstract: The Cre/loxP system has been used extensively for conditional mutagenesis in mice. Reporters of Cre activity are important for defining the spatial and temporal extent of Cre-mediated recombination. Here we describe mT/mG, a double-fluorescent Cre reporter mouse that expresses membrane-targeted tandem dimer Tomato (mT) prior to Cre-mediated excision and membrane-targeted green fluorescent protein (mG) after excision. We show that reporter expression is nearly ubiquitous, allowing visualization of fluorescent markers in live and fixed samples of all tissues examined. We further demonstrate that mG labeling is Cre-dependent, complementary to mT at single cell resolution, and distinguishable by fluorescence-activated cell sorting. Both membrane-targeted markers outline cell morphology, highlight membrane structures, and permit visualization of fine cellular processes. In addition to serving as a global Cre reporter, the mT/mG mouse may also be used as a tool for lineage tracing, transplantation studies, and analysis of cell morphology in vivo.
2,972 citations
TL;DR: The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
Abstract: It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
2,804 citations
"Hippo signaling impedes adult heart..." refers background or methods in this paper
...Data from human and mouse studies indicate that cardiomyocytes regenerate inefficiently at ~1% per year in young hearts (Bergmann et al., 2009; Kajstura et al., 2012; Mollova et al., 2013; Senyo et al., 2013)....
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...Nuclei isolation and flow analysis Nuclei isolation was performed as described previously (Bergmann et al., 2009)....
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...1C) (Bergmann et al., 2009)....
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TL;DR: It is found that the hearts of 1-day-old neonatal mice can regenerate after partial surgical resection, but this capacity is lost by 7 days of age, which means that for a brief period after birth, the mammalian heart appears to have the capacity to regenerate.
Abstract: Certain fish and amphibians retain a robust capacity for cardiac regeneration throughout life, but the same is not true of the adult mammalian heart. Whether the capacity for cardiac regeneration is absent in mammals or whether it exists and is switched off early after birth has been unclear. We found that the hearts of 1-day-old neonatal mice can regenerate after partial surgical resection, but this capacity is lost by 7 days of age. This regenerative response in 1-day-old mice was characterized by cardiomyocyte proliferation with minimal hypertrophy or fibrosis, thereby distinguishing it from repair processes. Genetic fate mapping indicated that the majority of cardiomyocytes within the regenerated tissue originated from preexisting cardiomyocytes. Echocardiography performed 2 months after surgery revealed that the regenerated ventricular apex had normal systolic function. Thus, for a brief period after birth, the mammalian heart appears to have the capacity to regenerate.
2,080 citations
TL;DR: It is found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes.
Abstract: Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes. Other studies suggest that new cardiomyocytes are born at a very low rate, and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse-chase approaches--genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry--that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.
1,146 citations
TL;DR: A nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size is uncovered.
Abstract: Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.
954 citations
"Hippo signaling impedes adult heart..." refers background or methods in this paper
...Previous cardiac loss-of-function studies in mice revealed that Hippo signaling inhibits cardiomyocyte proliferation during development to control heart size (Heallen et al., 2011)....
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...5cre transgenic line and floxed alleles for ww45/Salvador and lats12/Warts have been described previously (Heallen et al., 2011)....
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...Fixation, tissue processing, antigen retrieval and blocking for non-specific staining have been described previously (Heallen et al., 2011)....
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...5 cre driver, which inactivates Salv during development and is known to efficiently delete Salv (Heallen et al., 2011)....
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