Functional coordination of non‐myocytes plays a key role in adult zebrafish heart regeneration

EMBO Reports ◽  
2021 ◽  
Author(s):  
Hong Ma ◽  
Ziqing Liu ◽  
Yuchen Yang ◽  
Dong Feng ◽  
Yanhan Dong ◽  
...  
Keyword(s):  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Zebrafish Heart

scholarly journals Inhibition of let-7c Regulates Cardiac Regeneration after Cryoinjury in Adult Zebrafish

2019 ◽  
Vol 6 (2) ◽  
pp. 16 ◽  
Author(s):  
Suneeta Narumanchi ◽  
Karri Kalervo ◽  
Sanni Perttunen ◽  
Hong Wang ◽  
Katariina Immonen ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Regeneration ◽  
Nuclear Antigen ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Tissue Samples ◽  
Micro Rnas ◽  
Proliferating Cell ◽  
Zebrafish Heart

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration.

scholarly journals High-frequency dual mode pulsed wave Doppler imaging for monitoring the functional regeneration of adult zebrafish hearts

2015 ◽  
Vol 12 (103) ◽  
pp. 20141154 ◽  
Author(s):  
Bong Jin Kang ◽  
Jinhyoung Park ◽  
Jieun Kim ◽  
Hyung Ham Kim ◽  
Changyang Lee ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
High Frequency ◽  
Doppler Imaging ◽  
Flow Mode ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Dual Mode ◽  
Doppler Flow ◽  
Pulsed Wave Doppler ◽  
Zebrafish Heart

Adult zebrafish is a well-known small animal model for studying heart regeneration. Although the regeneration of scars made by resecting the ventricular apex has been visualized with histological methods, there is no adequate imaging tool for tracking the functional recovery of the damaged heart. For this reason, high-frequency Doppler echocardiography using dual mode pulsed wave Doppler, which provides both tissue Doppler (TD) and Doppler flow in a same cardiac cycle, is developed with a 30 MHz high-frequency array ultrasound imaging system. Phantom studies show that the Doppler flow mode of the dual mode is capable of measuring the flow velocity from 0.1 to 15 cm s −1 with high accuracy ( p -value = 0.974 > 0.05). In the in vivo study of zebrafish, both TD and Doppler flow signals were simultaneously obtained from the zebrafish heart for the first time, and the synchronized valve motions with the blood flow signals were identified. In the longitudinal study on the zebrafish heart regeneration, the parameters for diagnosing the diastolic dysfunction, for example, E / E m < 10, E / A < 0.14 for wild-type zebrafish, were measured, and the type of diastolic dysfunction caused by the amputation was found to be similar to the restrictive filling. The diastolic function was fully recovered within four weeks post-amputation.

scholarly journals Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Matthew Gemberling ◽  
Ravi Karra ◽  
Amy L Dickson ◽  
Kenneth D Poss
Keyword(s):  
Cardiac Injury ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Adult Zebrafish ◽  
Perivascular Cells ◽  
Adult Heart ◽  
Muscle Hyperplasia ◽  
Zebrafish Heart

Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.

scholarly journals Live imaging of adult zebrafish cardiomyocyte proliferation ex vivo

Development ◽  
2021 ◽  
Author(s):  
Hessel Honkoop ◽  
Phong D. Nguyen ◽  
Veronique E.M. van der Velden ◽  
Katharina F. Sonnen ◽  
Jeroen Bakkers
Keyword(s):  
Culture System ◽  
Ex Vivo ◽  
Live Imaging ◽  
Slice Culture ◽  
Heart Regeneration ◽  
Dependent Manner ◽  
Cardiomyocyte Proliferation ◽  
Adult Zebrafish ◽  
Cellular Mechanisms ◽  
Zebrafish Heart

Zebrafish are excellent at regenerating their heart by reinitiating proliferation in pre-existing cardiomyocytes. Studying how zebrafish achieve this holds great potential in developing new strategies to boost mammalian heart regeneration. Nevertheless, the lack of appropriate live imaging tools for the adult zebrafish heart has limited detailed studies into the dynamics underlying cardiomyocyte proliferation. Here, we address this by developing a system in which cardiac slices of the injured zebrafish heart are cultured ex vivo for several days while retaining key regenerative characteristics including cardiomyocyte proliferation. In addition, we show that the cardiac slice culture system is compatible with live timelapse imaging and allows manipulation of regenerating cardiomyocytes with drugs that normally would have toxic effects that prevent its use. Finally, we use the cardiac slices to demonstrate that adult cardiomyocytes with fully assembled sarcomeres can partially disassemble their sarcomeres in a calpain and proteasome dependent manner to progress through nuclear division and cytokinesis. In conclusion, we have developed a cardiac slice culture system, which allows imaging of native cardiomyocyte dynamics in real time to discover cellular mechanisms during heart regeneration.

scholarly journals Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration

2019 ◽  
Author(s):  
Anna Garcia-Puig ◽  
Jose Luis Mosquera ◽  
Senda Jiménez-Delgado ◽  
Cristina García-Pastor ◽  
Ignasi Jorba ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Dynamic Change ◽  
Protein Composition ◽  
Cytoskeletal Proteins ◽  
Heart Regeneration ◽  
Matrix Remodeling ◽  
Adult Zebrafish ◽  
Force Microscopy ◽  
Ecm Proteins ◽  
Zebrafish Heart

AbstractAdult zebrafish, in contrast to mammals, are able to regenerate their hearts in response to injury or experimental amputation. Our understanding of the cellular and molecular bases that underlie this process, although fragmentary, has increased significantly over the last years. However, the role of the extracellular matrix (ECM) during zebrafish heart regeneration has been comparatively rarely explored. Here, we set out to characterize the ECM protein composition in adult zebrafish hearts, and whether it changed during the regenerative response. For this purpose, we first established a decellularization protocol of adult zebrafish ventricles that significantly enriched the yield of ECM proteins. We then performed proteomic analyses of decellularized control hearts and at different times of regeneration. Our results show a dynamic change in ECM protein composition, most evident at the earliest (7 days post-amputation) time-point analyzed. Regeneration associated with sharp increases in specific ECM proteins, and with an overall decrease in collagens and cytoskeletal proteins. We finally tested by atomic force microscopy that the changes in ECM composition translated to decreased ECM stiffness. Our cumulative results identify changes in the protein composition and mechanical properties of the zebrafish heart ECM during regeneration.

scholarly journals Cellular drivers of injury response and regeneration in the adult zebrafish heart

2021 ◽  
Author(s):  
Bo Hu ◽  
Sara Lelek ◽  
Bastiaan Spanjaard ◽  
Mariana Guedes Simões ◽  
Hananeh Aliee ◽  
...  
Keyword(s):  
High Capacity ◽  
Fibroblast Cell ◽  
Cell Types ◽  
Spatiotemporal Analysis ◽  
Lineage Tracing ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Ability To Regenerate ◽  
Novel Therapeutic Strategies ◽  
Zebrafish Heart

Myocardial infarction is a leading cause of death worldwide, as the adult human heart does not have the ability to regenerate efficiently after insults. In contrast, the adult zebrafish heart has a high capacity for regeneration, and understanding the mechanisms of regenerative processes in fish allows identification of novel therapeutic strategies. While several pro-regenerative factors have been described, the cell types orchestrating heart regeneration remain largely elusive. To overcome this conceptual limitation, we dissected cell type diversity in the regenerating zebrafish heart based on single cell transcriptomics and spatiotemporal analysis. We discovered a dramatic induction of several pro-regenerative cell types with fibroblast characteristics. To understand the cascade of events leading to heart regeneration, we determined the origin of these cell types by high-throughput lineage tracing. We found that pro-regenerative fibroblasts are derived from two separate sources, the epicardium and the endocardium. Mechanistically, we identified Wnt signaling as a key regulator of the endocardial regenerative response. In summary, our results uncover specialized fibroblast cell types as major drivers of heart regeneration, thereby opening up new possibilities to interfere with the regenerative capacity of the vertebrate heart.

Pre-existent adult sox10+ cardiomyocytes contribute to myocardial regeneration in the zebrafish

2019 ◽  
Author(s):  
Marcos Sande-Melón ◽  
Inês J. Marques ◽  
María Galardi-Castilla ◽  
Xavier Langa ◽  
María Pérez-López ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Crucial Role ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Genetic Ablation ◽  
Fibrotic Tissue ◽  
Distinct Gene Expression Profile ◽  
Zebrafish Heart

AbstractDuring heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from pre-existing ones. It is unclear whether the heart is comprised of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, using sox10 genetic fate mapping, we identified a subset of pre-existent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded massively after cryoinjury. Genetic ablation of sox10+ cardiomyocytes severely impaired cardiac regeneration revealing that they play a crucial role for heart regeneration.

scholarly journals Fate predetermination of cardiac myocytes during zebrafish heart regeneration

Open Biology ◽  
2017 ◽  
Vol 7 (6) ◽  
pp. 170116 ◽  
Author(s):  
Isil Tekeli ◽  
Anna Garcia-Puig ◽  
Mario Notari ◽  
Cristina García-Pastor ◽  
Isabelle Aujard ◽  
...  
Keyword(s):  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Injury Site ◽  
Adult Heart ◽  
Ability To Regenerate ◽  
And Migration ◽  
Dynamic Plasticity ◽  
Zebrafish Heart ◽  
Myocardial Layer ◽  
Labelling System

Adult zebrafish have the remarkable ability to regenerate their heart upon injury, a process that involves limited dedifferentiation and proliferation of spared cardiomyocytes (CMs), and migration of their progeny. During regeneration, proliferating CMs are detected throughout the myocardium, including areas distant to the injury site, but whether all of them are able to contribute to the regenerated tissue remains unknown. Here, we developed a CM-specific, photoinducible genetic labelling system, and show that CMs labelled in embryonic hearts survive and contribute to all three (primordial, trabecular and cortical) layers of the adult zebrafish heart. Next, using this system to investigate the fate of CMs from different parts of the myocardium during regeneration, we show that only CMs immediately adjacent to the injury site contributed to the regenerated tissue. Finally, our results show an extensive predetermination of CM fate during adult heart regeneration, with cells from each myocardial layer giving rise to cells that retain their layer identity in the regenerated myocardium. Overall, our results indicate that adult heart regeneration in the zebrafish is a rather static process governed by short-range signals, in contrast to the highly dynamic plasticity of CM fates that takes place during embryonic heart regeneration.

scholarly journals Ccn2a/Ctgfa is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish

Development ◽  
2020 ◽  
pp. dev.193219
Author(s):  
Debanjan Mukherjee ◽  
Ganesh Wagh ◽  
Mayssa H. Mokalled ◽  
Zacharias Kontarakis ◽  
Amy L. Dickson ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Cardiac Regeneration ◽  
Regenerative Process ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Wild Type ◽  
Injured Tissue ◽  
Cellular Communication Network ◽  
Zebrafish Heart ◽  
Chemokine Receptor Gene

The ability of zebrafish to heal their heart after injury makes them an attractive model to investigate mechanisms governing the regenerative process. In this study, we show that the gene cellular communication network factor 2a (ccn2a), previously known as ctgfa, is induced in endocardial cells in the injured tissue and regulates CM proliferation and repopulation of the damaged tissue. We find that whereas in wild-type animals, CMs track along the newly formed blood vessels that revascularize the injured tissue, in ccn2a mutants CM proliferation and repopulation are disrupted despite apparently unaffected revascularization. In addition, we find that ccn2a overexpression enhances CM proliferation and improves the resolution of transient collagen deposition. Through loss- and gain-of-function as well as pharmacological approaches, we provide evidence that Ccn2a is necessary for and promotes heart regeneration by enhancing the expression of pro-regenerative extracellular matrix genes, and by inhibiting the chemokine receptor gene cxcr3.1 through a mechanism involving Tgfβ/pSmad3 signaling. Thus, Ccn2a positively modulates the innate regenerative response of the adult zebrafish heart.

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