scholarly journals Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish

2018 ◽  
Vol 115 (35) ◽  
pp. 8805-8810 ◽  
Author(s):  
Ravi Karra ◽  
Matthew J. Foglia ◽  
Wen-Yee Choi ◽  
Christine Belliveau ◽  
Paige DeBenedittis ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Injury ◽  
Angiogenic Factor ◽  
Regulatory Sequences ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Myocardial Wall ◽  
Tightly Coupled ◽  
Spatiotemporal Control

During heart development and regeneration, coronary vascularization is tightly coupled with cardiac growth. Although inhibiting vascularization causes defects in the innate regenerative response of zebrafish to heart injury, angiogenic signals are not known to be sufficient for triggering regeneration events. Here, by using a transgenic reporter strain, we found that regulatory sequences of the angiogenic factor vegfaa are active in epicardial cells of uninjured animals, as well as in epicardial and endocardial tissue adjacent to regenerating muscle upon injury. Additionally, we find that induced cardiac overexpression of vegfaa in zebrafish results in overt hyperplastic thickening of the myocardial wall, accompanied by indicators of angiogenesis, epithelial-to-mesenchymal transition, and cardiomyocyte regeneration programs. Unexpectedly, vegfaa overexpression in the context of cardiac injury enabled ectopic cardiomyogenesis but inhibited regeneration at the site of the injury. Our findings identify Vegfa as one of a select few known factors sufficient to activate adult cardiomyogenesis, while also illustrating how instructive factors for heart regeneration require spatiotemporal control for efficacy.

scholarly journals SRSF3 is a key regulator of epicardial formation

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.

scholarly journals Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury

2021 ◽  
Author(s):  
Aaaron H Wasserman ◽  
Yonatan R Lewis-Israeli ◽  
Amanda R Huang ◽  
McKenna D Dooley ◽  
Allison L Mitchell ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Heart Development ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Cardiac Injury ◽  
Cellular Reprogramming ◽  
Heart Regeneration ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Epicardial Cell

Cardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and frequently leads to massive heart injury and the loss of billions of cardiac muscle cells and associated vasculature. Critical work in the last two decades demonstrated that these lost cells can be partially regenerated by the epicardium, the outermost mesothelial layer of the heart, in a process that highly recapitulates its role in heart development. Upon cardiac injury, mature epicardial cells activate and undergo an epithelial-mesenchymal transition (EMT) to form epicardial-derived progenitor cells (EpiPCs), multipotent progenitors that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells. In mammals, this process alone is insufficient for significant regeneration, but it may be possible to prime it by administering specific reprogramming factors, leading to enhanced EpiPC function. Here, we show that oxytocin (OXT), a hypothalamic neuroendocrine peptide, induces epicardial cell proliferation, EMT, and migration in a mature-like model of human induced pluripotent stem cell (hiPSC)-derived epicardial cells. In addition, we demonstrate that OXT is released from the brain into the bloodstream after cardiac cryoinjury in zebrafish, eliciting significant epicardial activation and promoting heart regeneration. Oxytocin signaling is also critical for proper epicardium and myocardium development in zebrafish embryos. The above processes are significantly impaired when OXT signaling is inhibited chemically and genetically through RNA interference. Mechanistically, RNA sequencing analyses suggest that the transforming growth factor beta (TGF-β) pathway is the primary mediator of OXT-induced epicardial activation. Our research reveals for the first time a primarily brain-controlled mechanism that induces cellular reprogramming and regeneration of the injured heart, a finding that could yield significant translational advances for the treatment of CVD.

scholarly journals The Role of the Epicardium During Heart Development and Repair

2020 ◽  
Vol 126 (3) ◽  
pp. 377-394 ◽  
Author(s):  
Pearl Quijada ◽  
Michael A. Trembley ◽  
Eric M. Small
Keyword(s):  
Heart Development ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Injury ◽  
Single Layer ◽  
Mesenchymal Transition ◽  
Heart Repair ◽  
Heart Formation

The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.

Epicardial Cells of Human Adults Can Undergo an Epithelial-to-Mesenchymal Transition and Obtain Characteristics of Smooth Muscle Cells In Vitro

Stem Cells ◽  
2007 ◽  
Vol 25 (2) ◽  
pp. 271-278 ◽  
Author(s):  
John van Tuyn ◽  
Douwe E. Atsma ◽  
Elizabeth M. Winter ◽  
Ietje van der Velde-van Dijke ◽  
Daniel A. Pijnappels ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Muscle Cells ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Human Adults

scholarly journals Covering and Re-Covering the Heart: Development and Regeneration of the Epicardium

2018 ◽  
Vol 6 (1) ◽  
pp. 3 ◽  
Author(s):  
Yingxi Cao ◽  
Jingli Cao
Keyword(s):  
Heart Development ◽  
Progenitor Cell ◽  
Recent Progress ◽  
Cardiac Injury ◽  
Vital Role ◽  
Cardiac Repair ◽  
Heart Regeneration ◽  
Epicardial Cells ◽  
Cell Source ◽  
Signaling Center

The epicardium, a mesothelial layer that envelops vertebrate hearts, has become a therapeutic target in cardiac repair strategies because of its vital role in heart development and cardiac injury response. Epicardial cells serve as a progenitor cell source and signaling center during both heart development and regeneration. The importance of the epicardium in cardiac repair strategies has been reemphasized by recent progress regarding its requirement for heart regeneration in zebrafish, and by the ability of patches with epicardial factors to restore cardiac function following myocardial infarction in mammals. The live surveillance of epicardial development and regeneration using zebrafish has provided new insights into this topic. In this review, we provide updated knowledge about epicardial development and regeneration.

scholarly journals ATXN10 is required for embryonic heart development and maintenance of epithelial cell phenotypes in the adult kidney and pancreas

2021 ◽  
Author(s):  
Melissa R. Bentley-Ford ◽  
Reagan S. Andersen ◽  
Mandy J. Croyle ◽  
Courtney J. Haycraft ◽  
Kelsey R. Clearman ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Pancreatic Insufficiency ◽  
Joubert Syndrome ◽  
Embryonic Lethality ◽  
Mesenchymal Transition ◽  
Adult Mice ◽  
Adult Kidney ◽  
Cilia Formation ◽  
Acinar To Ductal Metaplasia

AbstractAtxn10 is a gene known for its role in cytokinesis during the cell cycle and is associated with Spinocerebellar Ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes Nephronophthisis (NPHP) and Joubert Syndrome (JBTS), which are caused by disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt Atxn10 systemically, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial to mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively this study identifies ATXN10 as an essential protein for survival.

scholarly journals ATXN10 Is Required for Embryonic Heart Development and Maintenance of Epithelial Cell Phenotypes in the Adult Kidney and Pancreas

2021 ◽  
Vol 9 ◽  
Author(s):  
Melissa R. Bentley-Ford ◽  
Reagan S. Andersen ◽  
Mandy J. Croyle ◽  
Courtney J. Haycraft ◽  
Kelsey R. Clearman ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Pancreatic Insufficiency ◽  
Joubert Syndrome ◽  
Embryonic Lethality ◽  
Mesenchymal Transition ◽  
Adult Mice ◽  
Adult Kidney ◽  
Cilia Formation ◽  
Acinar To Ductal Metaplasia

Atxn10 is a gene known for its role in cytokinesis and is associated with spinocerebellar ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes nephronophthisis (NPHP) and Joubert syndrome (JBTS), which are caused by the disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here, we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue-specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt ATXN10 systemically at postnatal stages, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial-to-mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively, this study identifies ATXN10 as an essential protein for survival.

Abstract 509: Oxytocin Mediates Neuroendocrine Reprogramming of the Epicardium in Heart Regeneration

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Aaron H Wasserman ◽  
Amanda R Huang ◽  
Aitor Aguirre
Keyword(s):  
Stem Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cardiac Injury ◽  
The United States ◽  
Cardiac Cells ◽  
Heart Regeneration ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Cell Counts

Cardiovascular disease (CVD) is the leading cause of mortality both in the United States and worldwide. CVD often results in the massive loss of contractile cardiac cells and tissue. Critical work in the last two decades demonstrates that lost cells can be partially replenished by the epicardium, the outermost mesothelial layer of the heart. Upon cardiac injury, mature epicardial cells activate and undergo epithelial-mesenchymal transition (EMT) to form epicardium-derived progenitor cells (EPDCs), which are a type of multipotent stem cell that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells. This process alone is insufficient for significant regeneration, but its efficiency can be improved by priming with specific factors (e.g., thymosin beta-4). Our group has recently discovered evidence that oxytocin (OT), a hypothalamic neuroendocrine peptide, induces a pro-regenerative phenotype in vitro in human induced pluripotent stem cell (iPSC) derived epicardial cells. We hypothesize that upon cardiac injury, oxytocin is released into the bloodstream, causing activation of the epicardium and mobilization of EPDCs to elicit regeneration of damaged tissue and restoration of function. Here, we show that we can differentiate mature, high-quality epicardial cells from iPSCs and that Ki67 levels and cell counts increase after three days of OT exposure. In addition, the peptide alters gene expression levels of several epithelial, mesenchymal, and EMT markers, indicating a transition to a dedifferentiated gene profile characteristic of EPDCs. Finally, when OT is administered intravenously to mice, it accelerates healing from cardiac injury by inducing epicardial activation. Future studies will aim to further reveal the physiological contribution of OT to heart regeneration in vivo and determine its molecular mechanism of action. Our findings have the potential to uncover a novel mechanism of neuroendocrine reprogramming of the injured heart and yield significant translational advances in the treatment of CVD.

Cardiac Repair: The Intricate Crosstalk between the Epicardium and the Myocardium

2020 ◽  
Vol 15 (8) ◽  
pp. 661-673
Author(s):  
Laura Pellegrini ◽  
Eleonora Foglio ◽  
Elena Pontemezzo ◽  
Antonia Germani ◽  
Matteo Antonio Russo ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Heart Diseases ◽  
Pericardial Fluid ◽  
Cardiac Repair ◽  
Bioactive Molecules ◽  
Ischemic Heart ◽  
Paracrine Factors ◽  
Mesenchymal Transition ◽  
Ischemic Heart Diseases ◽  
Epicardial Cells

Background: Substantial evidences support the hypothesis that the epicardium has a role in cardiac repair and regeneration in part providing, by epithelial to mesenchymal transition (EMT), progenitor cells that differentiate into cardiac cell types and in part releasing paracrine factors that contribute to cardiac repair. Besides cell contribution, a significant paracrine communication occurs between the epicardium and the myocardium that improves the whole regenerative response. Signaling pathways underlying this communication are multiple as well as soluble factors involved in cardiac repair and secreted both by myocardial and epicardial cells. Most recently, extracellular vesicles, i.e. exosomes, that accumulate in the pericardial fluid (PF) and are able to transport bioactive molecules (cytosolic proteins, mRNAs, miRNAs and other non-coding RNAs), have been also identified as potential mediators of epicardial-mediated repair following myocardial injury. Conclusions: This mini-review provides an overview of the epicardial-myocardial signaling in regulating cardiac repair in ischemic heart diseases. Indeed, a detailed understanding of the crosstalk between myocardial and epicardial cells and how paracrine mechanisms are involved in the context of ischemic heart diseases would be of tremendous help in developing novel therapeutic approaches to promote cardiomyocytes survival and heart regeneration following myocardial infarction (MI).

scholarly journals Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nan W. Hultgren ◽  
Jennifer S. Fang ◽  
Mary E. Ziegler ◽  
Ricardo N. Ramirez ◽  
Duc T. T. Phan ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Activation ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Endothelial Cell Activation ◽  
Mesenchymal Transition ◽  
Snail Family ◽  
Retinal Angiogenesis

Abstract Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.

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