<i>tcf21+</i> epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration

Kikuchi, Kazu; Gupta, Vikas; Wang, Jinhu; Holdway, Jennifer E.; Wills, Airon A.; Fang, Yi; Poss, Kenneth D.

doi:10.1242/dev.067041

Cited by 276 publications

(366 citation statements)

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“…It has been shown that epicardial cells are activated early after cryoinjury and partially repopulate the damaged area by 3 dpi (5, 6). To investigate whether any epicardial cells could be observed in the injured area by 15 hpi, we cryoinjured fish harboring the tcf21:DsRed2 transgene, which labels epicardial and epicardiumderived cells (EPDCs) (14). However, at 15 hpi, we did not observe any DsRed + cells in the damaged region, indicating that blood vessels enter the injury site before EPDCs (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Similar to the myocardium, following-injury epicardial cells exhibit morphological changes and reexpress developmental genes including raldh2 and tbx18 (11,12). The epicardium gives rise to myofibroblasts and perivascular cells (13,14), and epicardium-derived perivascular and smooth muscle cells support revascularization of the injured area in zebrafish and mammals (15,16). Following injury, new coronary vessels penetrate the damaged area (5,12,16) where the main source of new coronary endothelium is preexisting endothelium (17).…”

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confidence: 99%

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Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Marín-Juez

Marass

Gauvrit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

166

222

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Zebrafish have a remarkable capacity to regenerate their heart. Efficient replenishment of lost tissues requires the activation of different cell types including the epicardium and endocardium. A complex set of processes is subsequently needed to support cardiomyocyte repopulation. Previous studies have identified important determinants of heart regeneration; however, to date, how revascularization of the damaged area happens remains unknown. Here, we show that angiogenic sprouting into the injured area starts as early as 15 h after injury. To analyze the role of vegfaa in heart regeneration, we used vegfaa mutants rescued to adulthood by vegfaa mRNA injections at the one-cell stage. Surprisingly, vegfaa mutants develop coronaries and revascularize after injury. As a possible explanation for these observations, we find that vegfaa mutant hearts up-regulate the expression of potentially compensating genes. Therefore, to overcome the lack of a revascularization phenotype in vegfaa mutants, we generated fish expressing inducible dominant negative Vegfaa. These fish displayed minimal revascularization of the damaged area. In the absence of fast angiogenic revascularization, cardiomyocyte proliferation did not occur, and the heart failed to regenerate, retaining a fibrotic scar. Hence, our data show that a fast endothelial invasion allows efficient revascularization of the injured area, which is necessary to support replenishment of new tissue and achieve efficient heart regeneration. These findings revisit the model where neovascularization is considered to happen concomitant with the formation of new muscle. Our work also paves the way for future studies designed to understand the molecular mechanisms that regulate fast revascularization.heart regeneration | angiogenesis | revascularization | coronaries | VEGF

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Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Marín-Juez

Marass

Gauvrit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

166

222

View full text Add to dashboard Cite

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“…30 In embryos, the hypothesis of an alternative source for supplying cardiac progenitor cells from the epicardium was denied by a lineage-tracing study, confirming the possibility that the mechanism for embryonic heart growth is similar to that of juveniles. 31 What causes the heart failure response?…”

Section: Multiple Stressors Converge To Halt Cardiomyocyte Proliferationmentioning

confidence: 99%

Impaired Cardiovascular Function Caused by Different Stressors Elicits a Common Pathological and Transcriptional Response in Zebrafish Embryos

Chen

2013

Zebrafish

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Zebrafish embryos have been widely used to study the genes and processes needed for normal vertebrate heart development. We recently observed that exposure to 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) or retinoic acid (RA) produces very similar signs of heart failure in developing zebrafish via divergent molecular pathways. The fact that diverse stressors and mutations cause severe pericardial edema and circulatory collapse in developing zebrafish has been largely unexplored. We hypothesized that unrelated chemicals can trigger a common pathological response leading to the same end-stage heart failure. To test this hypothesis, we compared the effects of TCDD, RA, carbaryl, valproic acid, and morpholino oligonucleotide (MO) knockdown of TBX5 on the developing heart in zebrafish embryos. These model stressors have all been previously reported to affect zebrafish heart development, and elicited very similar signs of embryonic heart failure. Microarray analysis showed that one cluster of 92 transcripts affected by these different treatments was significantly downregulated by all treatments. This gene cluster is composed of transcripts required for chromosome assembly, DNA replication, and cell cycle progression. We refer to this cluster as the cell cycle gene cluster (CCGC). Immunohistochemistry revealed that downregulation of the CCGC precedes a halt in cardiomyocyte proliferation in the hearts of zebrafish exposed to any of the treatments. Previous work has shown that the initial response to TCDD is a decrease in cardiac output. Since this precedes the signs of edema, heart failure, and fall in CCGC expression, we postulated that any factor that decreases cardiac output will produce the same syndrome of heart failure responses. To test this, we used MO knockdown of cardiac troponin T2 (TNNT2) to specifically block contractility. The TNNT2-MO produced exactly the same signs of cardiotoxicity as the other treatments, including downregulation of the signature CCGC. Our results indicate that agents altering cardiac output can have amplified consequences during specific periods in development.

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“…Zebrafish hearts can fully regenerate within a period of 30 to 60 days after surgical removal of as much as 20% of the ventricle [71], a cryoinjury or a genetic ablation of over 60% of the cardiomyocytes [77 80]. Cardiac regeneration in adult zebrafish is not achieved by proliferation and differentiation of cardiac stem cells, as initially suggested, but by activation, de-differentiation and proliferation of mature cardiomyocytes [75,76,81]. After de-differentiation, cardiomyocytes undergo a subsequent maturation step to completely restore cardiac function.…”

Section: Epicardium and Cardiac Regenerationmentioning

confidence: 99%

“…After de-differentiation, cardiomyocytes undergo a subsequent maturation step to completely restore cardiac function. Ultimately, newly generated cardiac myocytes are functionally integrated with the preexisting myocardium with little or no evidence of the injury, suggesting complete myocardial regeneration [75,76,81]. These studies have encouraged scientists to determine whether the adult mammalian heart is incapable of cardiac myocyte replacement or whether it retains a low-level capacity for regeneration, which could be therapeutically amplified.…”

Section: Epicardium and Cardiac Regenerationmentioning

confidence: 99%

Epicardial Lineages and Cardiac Repair

Singh

Epstein

2013

JDB

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Abstract:The death of cardiac myocytes resulting from myocardial infarction is a major cause of heart failure worldwide. Effective therapies for regenerating lost cardiac myocytes are lacking. Recently, the epicardium has been implicated as a source of inflammatory cytokines, growth factors and progenitor cells that modulate the response to myocardial injury. During embryonic development, epicardially-derived cells have the potential to differentiate into multiple cardiac lineages, including fibroblasts, vascular smooth muscle and potentially other cell types. In the healthy adult heart, epicardial cells are thought to be generally quiescent. However, injury of the adult heart results in reactivation of a developmental gene program in the epicardium, which leads to increased epicardial cell proliferation and differentiation of epicardium-derived cells (EPDCs) into various cardiac lineages. Recent work suggests that epicardial reactivation after injury is accompanied by, and contributes to, a robust inflammatory response. In this review, we describe the current status of research related to epicardial biology in cardiac development and regeneration, highlighting important recent discoveries and ongoing controversies.

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tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration

Cited by 276 publications

References 34 publications

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Impaired Cardiovascular Function Caused by Different Stressors Elicits a Common Pathological and Transcriptional Response in Zebrafish Embryos

Epicardial Lineages and Cardiac Repair

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