scholarly journals Ctnna3 Deficiency Promotes Heart Regeneration by Enhancing Cardiomyocyte Proliferation in Neonatal Mice

2021 ◽  
Author(s):  
sha zou ◽  
Wuhou Dai ◽  
Jifen Li ◽  
Hongyan Wang ◽  
Wufan Tao
Keyword(s):  
Myocardial Regeneration ◽  
Heart Regeneration ◽  
Molecular Signaling ◽  
Proliferative Capacity ◽  
Cardiomyocyte Proliferation ◽  
Mammalian Heart ◽  
Neonatal Mice ◽  
Functional Interference

Abstract Heart regeneration requires renewal of lost cardiomyocytes. However, the mammalian heart loses its proliferative capacity soon after birth, and the molecular signaling underlying the loss of cardiac proliferation postnatally is not fully understood. Here we report that ablation of Ctnna3, coding for an αT-catenin protein and highly expressed in hearts, accelerated heart regeneration following heart apex resection in neonatal mice. Our results show that Ctnna3 deficiency enhances cardiomyocyte proliferation in hearts from P7 mice by upregulating Yap expression. Our study demonstrates that Ctnna3 deficiency is sufficient to promote heart regeneration and cardiomyocyte proliferation in neonatal mice and indicates that functional interference of α-catenins might help to stimulate myocardial regeneration after injury.

scholarly journals Fosl1 is vital to heart regeneration upon apex resection in adult Xenopus tropicalis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hai-Yan Wu ◽  
Yi-Min Zhou ◽  
Zhu-Qin Liao ◽  
Jia-Wen Zhong ◽  
You-Bin Liu ◽  
...  
Keyword(s):  
Early Stage ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Heart Regeneration ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Proliferation ◽  
Neonatal Mice ◽  
Heart Injury

AbstractCardiovascular disease is the leading cause of death in the world due to losing regenerative capacity in the adult heart. Frogs possess remarkable capacities to regenerate multiple organs, including spinal cord, tail, and limb, but the response to heart injury and the underlying molecular mechanism remains largely unclear. Here we demonstrated that cardiomyocyte proliferation greatly contributes to heart regeneration in adult X. tropicalis upon apex resection. Using RNA-seq and qPCR, we found that the expression of Fos-like antigen 1 (Fosl1) was dramatically upregulated in early stage of heart injury. To study Fosl1 function in heart regeneration, its expression was modulated in vitro and in vivo. Overexpression of X. tropicalis Fosl1 significantly promoted the proliferation of cardiomyocyte cell line H9c2. Consistently, endogenous Fosl1 knockdown suppressed the proliferation of H9c2 cells and primary cardiomyocytes isolated from neonatal mice. Taking use of a cardiomyocyte-specific dominant-negative approach, we show that blocking Fosl1 function leads to defects in cardiomyocyte proliferation during X. tropicalis heart regeneration. We further show that knockdown of Fosl1 can suppress the capacity of heart regeneration in neonatal mice, but overexpression of Fosl1 can improve the cardiac function in adult mouse upon myocardium infarction. Co-immunoprecipitation, luciferase reporter, and ChIP analysis reveal that Fosl1 interacts with JunB and promotes the expression of Cyclin-T1 (Ccnt1) during heart regeneration. In conclusion, we demonstrated that Fosl1 plays an essential role in cardiomyocyte proliferation and heart regeneration in vertebrates, at least in part, through interaction with JunB, thereby promoting expression of cell cycle regulators including Ccnt1.

scholarly journals Protocol for cryoinjury model in neonatal mice for heart regeneration and repair research

2021 ◽  
Vol 2 (3) ◽  
pp. 100623
Author(s):  
Yanli Zhao ◽  
Rong Chang ◽  
Changchun Zeng
Keyword(s):  
Heart Regeneration ◽  
Neonatal Mice

The impact of glucocorticoids on Neuregulin-1/ERBB2 signaling in cardiomyocyte proliferation and heart regeneration

2020 ◽  
Vol 140 ◽  
pp. 30
Author(s):  
Nicola Pianca ◽  
Francesca Pontis ◽  
Alla Aharonov ◽  
Chiara Bongiovanni ◽  
Martina Mazzeschi ◽  
...  
Keyword(s):  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Neuregulin 1 ◽  
The Impact ◽  
Erbb2 Signaling

scholarly journals A Systematic Exposition of Methods used for Quantification of Heart Regeneration after Apex Resection in Zebrafish

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 548 ◽  
Author(s):  
Helene Juul Belling ◽  
Wolfgang Hofmeister ◽  
Ditte Caroline Andersen
Keyword(s):  
Human Heart ◽  
Quantitative Methods ◽  
Heart Function ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Ability To Regenerate ◽  
Specific Proteins ◽  
Heart Injury ◽  
Whole Heart ◽  
Study Designs

Myocardial infarction (MI) is a worldwide condition that affects millions of people. This is mainly caused by the adult human heart lacking the ability to regenerate upon injury, whereas zebrafish have the capacity through cardiomyocyte proliferation to fully regenerate the heart following injury such as apex resection (AR). But a systematic overview of the methods used to evidence heart regrowth and regeneration in the zebrafish is lacking. Herein, we conducted a systematical search in Embase and Pubmed for studies on heart regeneration in the zebrafish following injury and identified 47 AR studies meeting the inclusion criteria. Overall, three different methods were used to assess heart regeneration in zebrafish AR hearts. 45 out of 47 studies performed qualitative (37) and quantitative (8) histology, whereas immunohistochemistry for various cell cycle markers combined with cardiomyocyte specific proteins was used in 34 out of 47 studies to determine cardiomyocyte proliferation qualitatively (6 studies) or quantitatively (28 studies). For both methods, analysis was based on selected heart sections and not the whole heart, which may bias interpretations. Likewise, interstudy comparison of reported cardiomyocyte proliferation indexes seems complicated by distinct study designs and reporting manners. Finally, six studies performed functional analysis to determine heart function, a hallmark of human heart injury after MI. In conclusion, our data implies that future studies should consider more quantitative methods eventually taking the 3D of the zebrafish heart into consideration when evidencing myocardial regrowth after AR. Furthermore, standardized guidelines for reporting cardiomyocyte proliferation and sham surgery details may be considered to enable inter study comparisons and robustly determine the effect of given genes on the process of heart regeneration.

scholarly journals In Vivo Activation of a Conserved MicroRNA Program Induces Mammalian Heart Regeneration

2014 ◽  
Vol 15 (6) ◽  
pp. 805
Author(s):  
Aitor Aguirre ◽  
Nuria Montserrat ◽  
Serena Zacchigna ◽  
Emmanuel Nivet ◽  
Tomoaki Hishida ◽  
...  
Keyword(s):  
Heart Regeneration ◽  
Mammalian Heart

Abstract 396: Regulation of Cardiomyocyte Proliferation by the Hippo Pathway and Dystrophin Complex

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yuka Morikawa ◽  
John Leach ◽  
Todd Heallen ◽  
Ge Tao ◽  
James F Martin
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Dna Synthesis ◽  
De Novo ◽  
Hippo Pathway ◽  
Myocardial Damage ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Heart Repair ◽  
The Hippo Pathway

Regeneration in mammalian hearts is limited due to the extremely low renewal rate of cardiomyocytes and their inability to reenter the cell cycle. In rodent hearts, endogenous regenerative capacity exists during development but is rapidly repressed after birth, at which time growth is by hypertrophy. During the developmental and neonatal periods, heart regeneration occurs through proliferation of pre-existing cardiomyocytes. Our approach of activating heart regeneration is to uncover the mechanisms responsible for repression of cardiomyocyte proliferation. The Hippo pathway controls heart size by repressing cardiomyocyte proliferation during development. By deleting Salv , a modulator of the Hippo pathway, we found that myocardial damage in postnatal and adult hearts was repaired both anatomically and functionally. This heart repair occurred primary through proliferation of preexisting cardiomyocytes. During repair, cardiomyocytes reenter the cell cycle; de novo DNA synthesis, karyokinesis, and cytokinesis all take place. The dystrophin glycoprotein complex (DGC) is essential for muscle maintenance by anchoring the cytoskeleton and extracellular matrix. Disruption of the DGC results in muscular dystrophies, including Duchenne muscular dystrophy, resulting in both skeletal and cardiac myopathies. Recently the DGC was shown to regulate cardiomyocyte proliferation and we found that the DGC and the Hippo pathway components directly interact. To address if the DGC and the Hippo pathway coordinately regulate cardiomyocyte proliferation, we conditionally deleted Salv in the mouse model of muscular dystrophy, the mdx line. We found that simultaneous disruption of both the DGC and Hippo pathway leads an increased de novo DNA synthesis and cytokinesis in cardiomyocytes after heart damage. Our findings provide new insights into the mechanisms leading to heart repair through proliferation of endogenous cardiomyocytes.

scholarly journals Hypoxia-induced myocardial regeneration

2017 ◽  
Vol 123 (6) ◽  
pp. 1676-1681 ◽  
Author(s):  
Wataru Kimura ◽  
Yuji Nakada ◽  
Hesham A. Sadek
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Systolic Heart Failure ◽  
Cardiac Regeneration ◽  
Oxygen Metabolism ◽  
Functional Improvement ◽  
Cardiomyocyte Proliferation ◽  
Mammalian Heart ◽  
Cell Cycle Reentry ◽  
And Oxidative Stress

The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration.

scholarly journals Extending the time window of mammalian heart regeneration by thymosin beta 4

2014 ◽  
Vol 18 (12) ◽  
pp. 2417-2424 ◽  
Author(s):  
Liu Rui ◽  
Nie Yu ◽  
Lian Hong ◽  
He Feng ◽  
Han Chunyong ◽  
...  
Keyword(s):  
Time Window ◽  
Heart Regeneration ◽  
Thymosin Beta 4 ◽  
Mammalian Heart

scholarly journals Navigating the Crossroads of Cell Therapy and Natural Heart Regeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Stefan Elde ◽  
Hanjay Wang ◽  
Y. Joseph Woo
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Trials ◽  
Cell Therapy ◽  
Cause Of Death ◽  
Natural Regeneration ◽  
Therapeutic Potential ◽  
Myocardial Regeneration ◽  
Heart Regeneration ◽  
Recent Developments

Cardiovascular disease remains the leading cause of death worldwide despite significant advances in our understanding of the disease and its treatment. Consequently, the therapeutic potential of cell therapy and induction of natural myocardial regeneration have stimulated a recent surge of research and clinical trials aimed at addressing this challenge. Recent developments in the field have shed new light on the intricate relationship between inflammation and natural regeneration, an intersection that warrants further investigation.

Abstract 214: TLR3 Mediates Neonatal Heart Repair and Regeneration Through Glycolysis-dependent YAP/TAZ Mediated miR-152 Expression

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Xiaohui Wang ◽  
Yuanping Hu ◽  
Tuanzhu Ha ◽  
John Kalbfleisch ◽  
Race Kao ◽  
...  
Keyword(s):  
Cardiac Metabolism ◽  
Poly I:C ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Neonatal Cardiomyocytes ◽  
Neonatal Heart ◽  
Heart Repair ◽  
Inhibition Of Glycolysis ◽  
Neonatal Cardiomyocyte

The neonatal heart possesses the capability of regenerating and repairing damaged myocardium which is lost when cardiac metabolism switches from predominate glycolysis to oxidative phosphorylation seven days after birth. We have observed that Toll-like receptor 3 (TLR3) deficient neonatal hearts exhibit impaired cardiac function and larger infarct size after myocardial infarction (MI). We also found that stimulation of neonatal cardiomyocytes with the TLR3 ligand, poly (I:C) significantly enhances glycolytic capacity. Our observation suggests that TLR3 is required for neonatal heart repair and regeneration of damaged myocardium. This study investigated the mechanisms by which TLR3 mediates neonatal heart regeneration and repair. Neonatal cardiomyocytes were isolated from one day old WT mice and treated with poly (I:C) (1μg/ml) for 12-36 hours. We observed that poly (I:C) treatment: i) significantly enhances glycolytic metabolism; ii) increases YAP/TAZ activation: iii) increases miR-152 expression; iv) suppresses expression of DNMT1 and p27kip1, and v) promotes cardiomyocyte proliferation. However, inhibition of glycolysis with 2-Deoxyglucose (2-DG) prevented poly (I:C)-induced YAP/TAZ activation and miR-152 expression in neonatal cardiomyocytes. Similarly, inhibition of YAP/TAZ activation with Verteprofin (VP) abolished poly (I:C) induced miR-152 expression and neonatal cardiomyocyte proliferation. To investigate the role of miR-152 in neonatal cardiomyocyte proliferation, we transfected neonatal cardiomyocytes with miR-152 mimics and observed that increased miR-152 levels significantly promotes neonatal cardiomyocyte proliferation. We also observed that transfection of neonatal cardiomyocytes with miR-152 mimics markedly suppresses the expression of DNMT1 and p27kip1. Inhibition of DNMT1 with 5Azcytidine significantly promotes neonatal cardiomyocyte proliferation. Finally, we observed that treatment of neonatal mice (n=6) with 2-DG abolished cardiac functional recovery 3 weeks after MI. We conclude that TLR3 is required for neonatal heart regeneration and repair after MI. The mechanisms involve glycolytic dependent activation of YAP/TAZ mediated by miR-152 which represses DNMT1/p27kip1 expression.

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