The multiple functions of the proepicardial/epicardial cell lineage in heart development

The epicardium is the outer cell layer of the vertebrate heart. In recent years, both the embryonic and adult epicardium have revealed unsuspected peculiarities and functions, which are essential for cardiac development. In this chapter we review the current literature on the epicardium, and describe its evolutionary origin, the mechanisms leading to the induction of its extracardiac progenitor tissue, the proepicardium, and the way in which the proepicardium is transferred to the heart to form the epicardium. We also describe the epicardial epithelial–mesenchymal transition from which mesenchymal cells originate, and the developmental fate of these cells, which contribute to the vascular, interstitial, valvular, and adipose tissue. Finally, we review the molecular interactions established between the epicardium and the myocardium, which are key for myocardial development and can also play a role in cardiac homeostasis. This chapter highlights how the epicardium has become a major protagonist in cardiac biology.

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Every Beat You Take—The Wilms′ Tumor Suppressor WT1 and the Heart

International Journal of Molecular Sciences ◽

10.3390/ijms22147675 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7675

Author(s):

Nicole Wagner ◽

Kay-Dietrich Wagner

Keyword(s):

Tumor Suppressor ◽

Heart Development ◽

Epithelial Mesenchymal Transition ◽

Cardiac Development ◽

Wilms Tumor ◽

Current Knowledge ◽

Adult Life ◽

Autonomous Nervous System ◽

Mesenchymal Transition ◽

Organ Systems

Nearly three decades ago, the Wilms’ tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review summarizes the results from many research groups which allowed to establish a relevant function for Wt1 in cardiac development and disease. During development, Wt1 is involved in fundamental processes as the formation of the epicardium, epicardial epithelial-mesenchymal transition, coronary vessel development, valve formation, organization of the cardiac autonomous nervous system, and formation of the cardiac ventricles. Wt1 is further implicated in cardiac disease and repair in adult life. We summarize here the current knowledge about expression and function of Wt1 in heart development and disease and point out controversies to further stimulate additional research in the areas of cardiac development and pathophysiology. As re-activation of developmental programs is considered as paradigm for regeneration in response to injury, understanding of these processes and the molecules involved therein is essential for the development of therapeutic strategies, which we discuss on the example of WT1.

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Embryonic development of the heart

Development ◽

10.1242/dev.22.3.333 ◽

1969 ◽

Vol 22 (3) ◽

pp. 333-348

Author(s):

Francis J. Manasek

Keyword(s):

Cell Layer ◽

Embryonic Heart ◽

Outer Cell ◽

Chick Embryos ◽

Myocardial Wall ◽

Undifferentiated Cells ◽

Epicardial Layer ◽

Outer Cell Layer ◽

Heart Wall

The mature heart may be thought of as consisting of three layers, endocardium, myocardium, and an outer investing tissue called the epicardium. During early formation of the tubular heart of chick embryos, at about the 8-somite stage, two tissue layers become clearly discernible with the light microscope: the endocardium and the developing myocardial wall. The outer epicardial layer does not appear until later in development. It is generally accepted that embryonic heart wall or ‘epimyocardium’ is composed of muscle and undifferentiated cells. As its name implies, the epimyocardium is thought to give rise to myocardium and epicardium. Kurkiewicz (1909) suggested that the epicardium was not an epimyocardial derivative but rather is formed from cells originating in the sinus venosus region, which migrate over the surface of the heart. Nevertheless, it has become generally accepted that the outer cell layer of the embryonic heart wall differentiates in situ to give rise to the definitive visceral epicardium (Patten, 1953).

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Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

Cancers ◽

10.3390/cancers12010147 ◽

2020 ◽

Vol 12 (1) ◽

pp. 147 ◽

Cited By ~ 2

Author(s):

Wook Jin

Keyword(s):

Fusion Proteins ◽

Epithelial Mesenchymal Transition ◽

Tumor Regression ◽

Acquired Resistance ◽

Cell Lineage ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Acquired Drug Resistance ◽

Mesenchymal Transition ◽

Trk Inhibitors

Tropomyosin receptor kinase (Trk) C contributes to the clinicopathology of a variety of human cancers, and new chimeric oncoproteins containing the tyrosine kinase domain of TrkC occur after fusion to the partner genes. Overexpression of TrkC and TrkC fusion proteins was observed in patients with a variety of cancers, including mesenchymal, hematopoietic, and those of epithelial cell lineage. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were involved in the regulation of TrkC expression through transcriptional and posttranscriptional alteration. Aberrant activation of TrkC and TrkC fusion proteins markedly induces the epithelial-mesenchymal transition (EMT) program, growth rate, tumorigenic capacity via constitutive activation of Ras-MAP kinase (MAPK), PI3K-AKT, and the JAK2-STAT3 pathway. The clinical trial of TrkC or TrkC fusion-positive cancers with newly developed Trk inhibitors demonstrated that Trk inhibitors were highly effective in inducing tumor regression in patients who do not harbor mutations in the kinase domain. Recently, there has been a progressive accumulation of mutations in TrkC or the TrkC fusion protein detected in the clinic and its related cancer cell lines caused by high-throughput DNA sequencing. Despite given the high overall response rate against Trk or Trk fusion proteins-positive solid tumors, acquired drug resistance was observed in patients with various cancers caused by mutations in the Trk kinase domain. To overcome acquired resistance caused by kinase domain mutation, next-generation Trk inhibitors have been developed, and these inhibitors are currently under investigation in clinical trials.

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HEG1 indicates poor prognosis and promotes hepatocellular carcinoma invasion, metastasis, and EMT by activating Wnt/β-catenin signaling

Clinical Science ◽

10.1042/cs20190225 ◽

2019 ◽

Vol 133 (14) ◽

pp. 1645-1662 ◽

Cited By ~ 7

Author(s):

Yan-rong Zhao ◽

Ji-long Wang ◽

Cong Xu ◽

Yi-ming Li ◽

Bo Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Heart Development ◽

Poor Prognosis ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Disease Free Survival ◽

Intrahepatic Metastasis ◽

Mesenchymal Transition

Abstract Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and promotes intrahepatic metastasis, lung metastasis and EMT in vivo. Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.

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Zyxin Mediates Actin Fiber Reorganization in Epithelial–Mesenchymal Transition and Contributes to Endocardial Morphogenesis

Molecular Biology of the Cell ◽

10.1091/mbc.e09-01-0046 ◽

2009 ◽

Vol 20 (13) ◽

pp. 3115-3124 ◽

Cited By ~ 40

Author(s):

Masaki Mori ◽

Hironori Nakagami ◽

Nobutaka Koibuchi ◽

Koichi Miura ◽

Yoichi Takami ◽

...

Keyword(s):

Cell Motility ◽

Heart Development ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Focal Adhesions ◽

Atrioventricular Canal ◽

Actin Reorganization ◽

Mesenchymal Transition ◽

Actin Fiber ◽

Tgf Β1

Epithelial–mesenchymal transition (EMT) confers destabilization of cell–cell adhesion and cell motility required for morphogenesis or cancer metastasis. Here we report that zyxin, a focal adhesion-associated LIM protein, is essential for actin reorganization for cell migration in TGF-β1–induced EMT in normal murine mammary gland (NMuMG) cells. TGF-β1 induced the relocation of zyxin from focal adhesions to actin fibers. In addition, TGF-β1 up-regulated zyxin via a transcription factor, Twist1. Depletion of either zyxin or Twist1 abrogated the TGF-β1–dependent EMT, including enhanced cell motility and actin reorganization, indicating the TGF-β1-Twist1-zyxin signal for EMT. Both zyxin and Twist1 were predominantly expressed in the cardiac atrioventricular canal (AVC) that undergoes EMT during heart development. We further performed ex vivo AVC explant assay and revealed that zyxin was required for the reorganization of actin fibers and migration of the endocardial cells. Thus, zyxin reorganizes actin fibers and enhances cell motility in response to TGF-β1, thereby regulating EMT.

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The nervous system of the neotropical millipede Gymnostreptus olivaceus Schubart, 1944 (Spirostreptida, Spirostreptidae) shows an additional cell layer

Animal Biology ◽

10.1163/15707563-00002466 ◽

2015 ◽

Vol 65 (2) ◽

pp. 133-150 ◽

Cited By ~ 1

Author(s):

Annelise Francisco ◽

Roberta C.F. Nocelli ◽

Carmem S. Fontanetti

Keyword(s):

Nervous System ◽

Cell Layer ◽

Cortical Layer ◽

Morphological Description ◽

Outer Cell ◽

Olfactory Glomeruli ◽

Additional Cell ◽

The Central Nervous System ◽

Inner Region ◽

Outer Cell Layer

This study presents a morphological description of the central nervous system of the neotropical millipede Gymnostreptus olivaceus and the first report of an outer cell layer surrounding the nervous system in Diplopoda. The nervous system of this species consists of a brain formed by the fusion of proto-, deuto- and tritocerebrum, as well as a ventral nerve cord with metamerically arranged ganglia that extends through the entire length of the animal’s body. The optic lobes, mushroom bodies and olfactory glomeruli of this species were located and described. As has been reported for other millipedes, the nervous system of G. olivaceus comprises a cortical layer in which three types of neurons could be identified and an inner region of neuropil, both of which are wrapped and protected by a perineurium and a neural lamella. However, more externally to the neural lamella, there is a discontinuous and irregular outer cell sheath layer containing distinctive cells whose function appears to be linked to the nutrition and protection of neurons.

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Epidermis: Outer Cell Layer of the Plant

SciVee ◽

10.4016/19589.01 ◽

2010 ◽

Keyword(s):

Cell Layer ◽

Outer Cell ◽

Outer Cell Layer

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The molecular basis of cardiac embryogenesis

ESC CardioMed ◽

10.1093/med/9780198784906.003.0005 ◽

2018 ◽

pp. 36-39

Author(s):

Miguel Torres

Keyword(s):

Heart Development ◽

Molecular Basis ◽

Cardiac Development ◽

Current Knowledge ◽

Cell Lineage ◽

Postnatal Period ◽

Circulatory Support ◽

Lineage Specification ◽

Mammalian Embryo ◽

Chromatin Regulators

The heart is the first organ to function in the mammalian embryo; however, heart development spans the whole intrauterine period and is only completed during the postnatal period. The ability of the mammalian fetal heart to provide circulatory support while preserving its proliferative and regenerative ability has stimulated interest in the molecular and cellular pathways underlying cardiac development and how they might be exploited in the design of regenerative strategies in the adult heart. Cardiac cell lineage specification and differentiation is regulated by an intricate network of molecular pathways that involve extracellular signals, transcription factors, and chromatin regulators. This chapter outlines current knowledge and the latest advances in understanding the molecular basis of cardiac lineage specification and differentiation during embryonic development.

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Tumor Suppressive Effects of miR-124 and Its Function in Neuronal Development

International Journal of Molecular Sciences ◽

10.3390/ijms22115919 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5919

Author(s):

Rikako Sanuki ◽

Tomonori Yamamura

Keyword(s):

Target Genes ◽

Neuronal Development ◽

Epithelial Mesenchymal Transition ◽

Cell Lineage ◽

Suppressive Effect ◽

Breast Cancers ◽

Mesenchymal Transition ◽

Cell Metastasis ◽

Wide Range ◽

Cancer Types

MicroRNA-124 (miR-124) is strongly expressed in neurons, and its expression increases as neurons mature. Through DNA methylation in the miR-124 promoter region and adsorption of miR-124 by non-coding RNAs, miR-124 expression is known to be reduced in many cancer cells, especially with high malignancy. Recently, numerous studies have focused on miR-124 due to its promising tumor-suppressive effects; however, the overview of their results is unclear. We surveyed the tumor-suppressive effect of miR-124 in glial cell lineage cancers, which are the most frequently reported cancer types involving miR-124, and in lung, colon, liver, stomach, and breast cancers, which are the top five causes of cancer death. Reportedly, miR-124 not only inhibits proliferation and accelerates apoptosis, but also comprehensively suppresses tumor malignant transformation. Moreover, we found that miR-124 exerts its anti-tumor effects by regulating a wide range of target genes, most notably STAT3 and EZH2. In addition, when compared to the original role of miR-124 in neuronal development, we found that the miR-124 target genes that contribute to neuronal maturation share similarities with genes that cause cancer cell metastasis and epithelial-mesenchymal transition. We believe that the two apparently unrelated fields, cancer and neuronal development, can bring new discoveries to each other through the study of miR-124.

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SRSF3 is a key regulator of epicardial formation

10.1101/2021.11.25.470003 ◽

2021 ◽

Author(s):

Irina-Elena Lupu ◽

Andia Nicole Redpath ◽

Nicola Smart

Keyword(s):

Heart Development ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Cellular Proliferation ◽

Rna Binding ◽

Cardiac Development ◽

Cardiac Fibroblasts ◽

Mesenchymal Transition ◽

Epicardial Cells ◽

Epicardial Layer

The epicardium is a fundamental regulator of cardiac development, functioning to secrete essential growth factors and to produce epicardium-derived cells (EPDCs) that contribute most coronary vascular smooth muscle cells and cardiac fibroblasts. The molecular mechanisms that control epicardial formation and proliferation have not been fully elucidated. In this study, we found that the RNA-binding protein SRSF3 is highly expressed in the proepicardium and later in the epicardial layer during heart development. Deletion of Srsf3 from the murine proepicardium using the Tg(Gata5-Cre) or embryonic day (E) 8.5 induction of Wt1CreERT2 led to proliferative arrest and impaired epithelial-to-mesenchymal transition (EMT), which prevented proper formation and function of the epicardial layer. Induction of Srsf3 deletion with the Wt1CreERT2 after the proepicardial stage resulted in impaired EPDC formation and epicardial proliferation at E13.5. Single-cell RNA-sequencing showed SRSF3-depleted epicardial cells were removed by E15.5 and the remaining non-recombined cells became hyperproliferative and compensated for the loss via up-regulation of Srsf3. This research identifies SRSF3 as a master regulator of cellular proliferation in epicardial cells.

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