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Defective coronary network function and insufficient blood supply are both cause and consequence of myocardial infarction. Efficient revascularization after infarction is essential to support tissue repair and function. Zebrafish hearts exhibit a remarkable ability to regenerate, and coronary revascularization initiates within hours of injury, but how this process is regulated remains unknown. Here, we show that revascularization requires a coordinated multi-tissue response culminating with the formation of a complex vascular network available as a scaffold for cardiomyocyte repopulation. During a process we term "coronary-endocardial anchoring," new coronaries respond by sprouting (1) superficially within the regenerating epicardium and (2) intra-ventricularly toward the activated endocardium. Mechanistically, superficial revascularization is guided by epicardial Cxcl12-Cxcr4 signaling and intra-ventricular sprouting by endocardial Vegfa signaling. Our findings indicate that the injury-activated epicardium and endocardium support cardiomyocyte replenishment initially through the guidance of coronary sprouting. Simulating this process in the injured mammalian heart should help its healing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neutrophils are the first line defenders in the innate immune response, and rapidly migrate to an infected or injured area. Recently, bidirectional migration of neutrophils to the wound and the corresponding functions have become popular research pursuits. In zebrafish larvae, CXCR1/CXCL8 is the predominant chemoattractant pathway to recruit neutrophil to wound, while CXCR2/CXCL8 pathway mediate neutrophil dispersal in wound after injury. Here, we found that both CXCR1/CXCL8 and LTB4/BLT1 signals are activated in zebrafish heart after cryoinjury. And with a CXCR1/2 selective inhibitor (SB225002) treatment, the recruitment of neutrophils was not affected, but reverse migration of neutrophils was inhibited after cryoinjury of heart. We suggested that the neutrophil recruitment to cryoinjured area might be mediated by LTB4/BLT1 signals at the presence of SB225002. Therefore, SB225002 treatment resulted more accumulation and long retention of neutrophils in the injured heart. The long retention of neutrophils in the wound promoted revascularization in the injured heart; however, the AKT/mTOR pathway was inhibited and the regeneration was impaired. Our findings suggest that retention of neutrophils is a well-orchestrated process and might regulate regeneration by the AKT/mTOR pathway., (Copyright © 2019. Published by Elsevier Ltd.)

During heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from preexisting ones. It is unclear whether the heart is composed of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, using sox10 genetic fate mapping, we identify a subset of preexistent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded after cryoinjury. Genetic ablation of sox10 + cardiomyocytes impairs cardiac regeneration, revealing that these cells play a role in heart regeneration., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Deciphering the genetic and epigenetic regulation of cardiomyocyte proliferation in organisms that are capable of robust cardiac renewal, such as zebrafish, represents an attractive inroad towards regenerating the human heart. Using integrated high-throughput transcriptional and chromatin analyses, we have identified a strong association between H3K27me3 deposition and reduced sarcomere and cytoskeletal gene expression in proliferative cardiomyocytes following cardiac injury in zebrafish. To move beyond an association, we generated an inducible transgenic strain expressing a mutant version of histone 3, H3.3 K27M , that inhibits H3K27me3 catalysis in cardiomyocytes during the regenerative window. Hearts comprising H3.3 K27M -expressing cardiomyocytes fail to regenerate, with wound edge cells showing heightened expression of structural genes and prominent sarcomeres. Although cell cycle re-entry was unperturbed, cytokinesis and wound invasion were significantly compromised. Collectively, our study identifies H3K27me3-mediated silencing of structural genes as requisite for zebrafish heart regeneration and suggests that repression of similar structural components in the border zone of an infarcted human heart might improve its regenerative capacity., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Adult 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 postamputation) 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., (© 2019 Garcia-Puig et al.)

The stimulation of myocardium repair is restricted due to the limited understanding of heart regeneration. Interestingly, endogenous opioid peptides such as dynorphins and enkephalins are suggested to support this process. However, the mechanism-whether through the stimulation of the regenerative capacity of cardiac stem cells or through effects on other cell types in the heart-is still not completely understood. Thus, a model of the spontaneous cardiomyogenic differentiation of mouse embryonic stem (mES) cells via the formation of embryoid bodies was used to describe changes in the expression and localization of opioid receptors within cells during the differentiation process and the potential of the selected opioid peptides, dynorphin A and B, and methionin-enkephalins and leucin-enkephalins, to modulate cardiomyogenic differentiation in vitro. The expressions of both κ- and δ-opioid receptors significantly increased during mES cell differentiation. Moreover, their primary colocalization with the nucleus was followed by their growing presence on the cytoplasmic membrane with increasing mES cell differentiation status. Interestingly, dynorphin B enhanced the downregulation gene expression of Oct4 characteristic of the pluripotent phenotype. Further, dynorphin B also increased cardiomyocyte-specific Nkx2.5 gene expression. However, neither dynorphin A nor methionin-enkephalins and leucin-enkephalins exhibited any significant effects on the course of mES cell differentiation. In conclusion, despite the increased expression of opioid receptors and some enhancement of mES cell differentiation by dynorphin B, the overall data do not support the notion that opioid peptides have a significant potential to promote the spontaneous cardiomyogenesis of mES cells in vitro., (© 2018 Wiley Periodicals, Inc.)

The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ischemic lesions of the heart, including myocardial infarction, are the most common pathologies of human cardiovascular system. Despite all the research and achievements of medicine in this field, the mortality from this disease remains heavy. Therefore, studying of processes occurring in the myocardium in the early and late postinfarction periods remains important. Rat left ventricular cardiomyocyte (CMC) ploidy, hypertrophy, hyperplasia, and ultrastructure were investigated in 2, 6, and 26 weeks after experimental myocardial infarction, caused by permanent ligation of left coronary artery. Cytofluorimetric study of CMC ploidy revealed no difference between normal, sham-operated, and infarcted animals for all the tested stages. However, interference microscopy indicated significant changes in cells size. CMC dry mass of infarcted rats in 2 weeks after surgery was 1.5 times lower than in control and sham operated groups. Electron microscopy analysis of CMC revealed disruption of sarcomere structure. However, in 6 weeks after surgery CMC dry mass was 1.6 times higher than in control. In 26 weeks after myocardial infarction CMC dry mass exceeded control only in peri-infarction zone. Cell counting showed that the number of left ventricular CMC, reduced as a result of myocardial infarction, was not restored during myocardial remodeling. © 2019 International Society for Advancement of Cytometry., (© 2019 International Society for Advancement of Cytometry.)

Pluripotent stem cells (PSCs) are an attractive, reliable source for generating functional cardiomyocytes for regeneration of infarcted heart. However, inefficient cell engraftment into host tissue remains a notable challenge to therapeutic success due to mechanical damage or relatively inhospitable microenvironment. Evidence has shown that excessively formed scar tissues around cell delivery sites present as mechanical and biological barriers that inhibit migration and engraftment of implanted cells. In this review, we focus on the functional responses of stem cells and cardiomyocytes during the process of cardiac fibrosis and scar formation. Survival, migration, contraction, and coupling function of implanted cells may be affected by matrix remodeling, inflammatory factors, altered tissue stiffness, and presence of electroactive myofibroblasts in the fibrotic microenvironment. Although paracrine factors from implanted cells can improve cardiac fibrosis, the transient effect is insufficient for complete repair of an infarcted heart. Furthermore, investigation of interactions between implanted cells and fibroblasts including myofibroblasts helps the identification of new targets to optimize the host substrate environment for facilitating cell engraftment and functional integration. Several antifibrotic approaches, including the use of pharmacological agents, gene therapies, microRNAs, and modified biomaterials, can prevent progression of heart failure and have been developed as adjunct therapies for stem cell-based regeneration. Investigation and optimization of new biomaterials is also required to enhance cell engraftment of engineered cardiac tissue and move PSCs from a laboratory setting into translational medicine., (© 2019 The Authors. Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2019.)

The neonatal mouse heart is capable of transiently regenerating after injury from postnatal day (P) 0-7 and macrophages are found important in this process. However, whether macrophages alone are sufficient to orchestrate this regeneration; what regulates cardiomyocyte proliferation; why cardiomyocytes do not proliferate after P7; and whether adaptive immune cells such as regulatory T-cells (Treg) influence neonatal heart regeneration have less studied. Methods : We employed both loss- and gain-of-function transgenic mouse models to study the role of Treg in neonatal heart regeneration. In loss-of-function studies, we treated mice with the lytic anti-CD25 antibody that specifically depletes Treg; or we treated FOXP3 DTR with diphtheria toxin that specifically ablates Treg. In gain-of-function studies, we adoptively transferred hCD2 + Treg from NOD. Foxp3 hCD2 to NOD/SCID that contain Treg as the only T-cell population. Furthermore, we performed single-cell RNA-sequencing of Treg to uncover paracrine factors essential for cardiomyocyte proliferation. Results : Our results demonstrate a regenerative role of Treg in neonatal heart regeneration. Treg can directly facilitate cardiomyocyte proliferation in a paracrine manner.Conclusion : Our results demonstrate a regenerative role of Treg in neonatal heart regeneration. Treg can directly facilitate cardiomyocyte proliferation in a paracrine manner., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low fibroblast-cardiomyocyte conversion rates remain a major challenge in this reprogramming. To this end, here we conducted a chemical screen and identified four agents, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-β inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, which coordinately enhanced reprogramming efficiency. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we observed that the IMAP treatment increases iCM formation 6-fold. IMAP stimulated higher cardiac troponin T and α-actinin expression and increased sarcomere formation, coinciding with up-regulated expression of many cardiac genes and down-regulated fibroblast gene expression. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we also observed that the IMAP treatment repressed many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways. We therefore investigated the roles of C-C motif chemokine ligand 3 (CCL3), CCL6, and CCL17 in cardiac reprogramming and observed that they inhibited iCM formation, whereas inhibitors of C-C motif chemokine receptor 1 (CCR1), CCR4, and CCR5 had the opposite effect. These results indicated that the IMAP treatment directly suppresses specific C-C chemokine signaling pathways and thereby enhances cardiac reprogramming. In conclusion, a combination of four chemicals, named here IMAP, suppresses specific C-C chemokine signaling pathways and facilitates Mef2c/Gata4/Tbx5 (MGT)-induced cardiac reprogramming, providing a potential means for iCM formation in clinical applications., (© 2019 Guo et al.)

One great achievement in medical practice is the reduction in acute mortality of myocardial infarction due to identifying risk factors, antiplatelet therapy, optimized hospitalization and acute percutaneous coronary intervention. Yet, the prevalence of heart failure is increasing presenting a major socio-economic burden. Thus, there is a great need for novel therapies that can reverse damage inflicted to the heart. In recent years, data have accumulated suggesting that induction of cardiomyocyte proliferation might be a future option for cardiac regeneration. Here, we review the relevant literature since September 2015 concluding that it remains a challenge to verify that a therapy induces indeed cardiomyocyte proliferation. Most importantly, it is unclear that the detected increase in cardiomyocyte cell cycle activity is required for an associated improved function. In addition, we review the literature regarding the evidence that binucleated and polyploid mononucleated cardiomyocytes can divide, and put this in context to other cell types. Our analysis shows that there is significant evidence that binucleated cardiomyocytes can divide. Yet, it remains elusive whether also polyploid mononucleated cardiomyocytes can divide, how efficient proliferation of binucleated cardiomyocytes can be induced, what mechanism regulates cell cycle progression in these cells, and what fate and physiological properties the daughter cells have. In summary, we propose to standardize and independently validate cardiac regeneration studies, encourage the field to study the proliferative potential of binucleated and polyploid mononucleated cardiomyocytes, and to determine whether induction of polyploidization can enhance cardiac function post-injury., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Inflammation plays a crucial role in cardiac regeneration. Numerous advantages, including a robust regenerative ability, make the zebrafish a popular model to study cardiovascular diseases. The zebrafish breakdance (bre) mutant shares several key features with human long QT syndrome that predisposes to ventricular arrhythmias and sudden death. However, how inflammatory response and tissue regeneration following cardiac damage occur in bre mutant is unknown. Here, we have found that inflammatory response related genes were markedly expressed in the injured heart and excessive leukocyte accumulation occurred in the injured area of the bre mutant zebrafish. Furthermore, bre mutant zebrafish exhibited aberrant apoptosis and impaired heart regenerative ability after ventricular cryoinjury. Mild dosages of anti-inflammatory or prokinetic drugs protected regenerative cells from undergoing aberrant apoptosis and promoted heart regeneration in bre mutant zebrafish. We propose that immune or prokinetic therapy could be a potential therapeutic regimen for patients with genetic long QT syndrome who suffers from myocardial infarction., (Copyright © 2019. Published by Elsevier Ltd.)

The reprogramming of induced cardiomyocytes (iCMs) has shown potential in regenerative medicine. However, in vivo reprogramming of iCMs is significantly inefficient, and novel gene delivery systems are required to more efficiently and safely induce in vivo reprogramming of iCMs for therapeutic applications in heart injury. In this study, we show that cationic gold nanoparticles (AuNPs) loaded with Gata4, Mef2c, and Tbx5 function as nanocarriers for cardiac reprogramming. The AuNP/GMT/PEI nanocomplexes show high reprogramming efficiency in human and mouse somatic cells with low cytotoxicity and direct conversion into iCMs without integrating factors into the genome. Importantly, AuNP/GMT/PEI nanocomplexes led to efficient in vivo conversion into cardiomyocytes after myocardial infarction (MI), resulting in the effective recovery of cardiac function and scar area. Taken together, these results show that the AuNP/GMT/PEI nanocarrier can be used to develop effective therapeutics for heart regeneration in cardiac disease patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Long noncoding RNAs (lncRNAs) play important roles in the regulation of genes involved in cell proliferation. We have previously sought to more globally understand the differences of lncRNA expression between human fetal heart and adult heart to identify some functional lncRNAs which involve in the process of heart repair. We found that a highly conserved long noncoding RNA NR_045363 was mainly expressed in cardiomyocytes and rarely in non-cardiomyocytes. NR_045363 overexpression in 7-day-old mice heart could improve cardiac function and stimulate cardiomyocyte proliferation after myocardial infarction. Furthermore, NR_045363 knockdown inhibited proliferation of primary embryonic cardiomyocytes, while NR_045363 overexpression enhanced DNA synthesis and cytokinesis in neonatal cardiomyocytes in vitro. Mechanistic analysis revealed that NR_045363 promoted cardiomyocyte proliferation through interaction with miR-216a, which regulated the JAK2-STAT3 pathway. Our results showed that NR_045363 is a potent lncRNA modulator essential for cardiomyocyte proliferation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Stimulating cardiomyocyte regeneration after an acute injury remains the central goal in cardiovascular regenerative biology. While adult mammals respond to cardiac damage with deposition of rigid scar tissue, adult zebrafish and salamander unleash a regenerative program that culminates in new cardiomyocyte formation, resolution of scar tissue, and recovery of heart function. Recent studies have shown that immune cells are key to regulating pro-inflammatory and pro-regenerative signals that shift the injury microenvironment toward regeneration. Defining the genetic regulators that control the dynamic interplay between immune cells and injured cardiac tissue is crucial to decoding the endogenous mechanism of heart regeneration. In this review, we discuss our current understanding of the extent that macrophage and regulatory T cells influence cardiomyocyte proliferation and how microRNAs (miRNAs) regulate their activity in the injured heart.

This review deals with the human adult cardiomyocyte proliferation as a potential source for heart repair after injury. The mechanism to regain the proliferative capacity of adult cardiomyocytes is a challenge. However, recent studies are promising in showing that the 'locked' cell cycle of adult cardiomyocytes could be released through modulation of cell cycle checkpoints. In support of this are the signaling pathways of Notch, Hippo, Wnt, Akt and Jak/Stat that facilitate or inhibit the transition at cell cycle checkpoints. Cyclins and cyclin dependant kinases (CDKs) facilitate this transition which in turn is regulated by inhibitory action of pocket protein e.g. p21, p27 and p57. Transcription factors e.g. E2F, GATA4, TBx20 up regulate Cyclin A, A2, D, E, and CDK4 as promoters of cell cycle and Meis-1 and HIF-1 alpha down regulate cyclin D and E to inhibit the cell cycle. Paracrine factors like Neuregulin-1, IGF-1 and Oncostatin M and Extracellular Matrix proteins like Agrin have been involved in cardiomyocyte proliferation and dedifferentiation processes. A molecular switch model is proposed that transforms the post mitotic cell into an actively dividing cell. This model shows how the cell cycle is regulated through on- and off switch mechanisms through interaction of transcription factors and signaling pathways with proteins of the cell cycle checkpoints. Signals triggered by injury may activate the right combination of the various pathways that can 'switch on' the proliferation signals leading to myocardial regeneration.

Stem cells are the specialized cell population with unique self-renewal ability and act as the precursor of all the body cells. Broadly, stem cells are of two types one is embryonic stem cells while the other is adult or somatic stem cells. Embryonic stem cells are the cells of zygote of the blastocyst which give rise to all kind of body cells including embryonic cells, and it can reconstruct a complete organism. While the adult stem cells have limited differentiation ability in comparison with embryonic stem cells and it proliferates into some specific kind of cells. This unique ability of the stem cell makes it a compelling biomedical and therapeutic tool. Stem cells primarily serve as regenerative medicine for particular tissue regeneration or the whole organ regeneration in any physical injury or disease condition (like diabetes, cancer, periodontal disorder, etc.), tissue grafting and plastic surgery, etc. Along with this, it is also used in various preclinical and clinical investigations, biomedical engineering and as a potential diagnostic tool (such as the development of biomarkers) for non-invasive diagnosis of severe disorders. In this review article, we have summarized the application of stem cell as regenerative medicine and in the treatment of various chronic diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Myocardial infarction occurs as a result of acute arteriosclerotic plaque rupture in the coronary artery, triggering strong inflammatory responses. The necrotic cardiomyocytes are gradually replaced with noncontractile scar tissue that eventually manifests as heart failure. Pluripotent stem cells (PSCs) show great promise for widespread clinical applications, particularly for tissue regeneration, and are being actively studied around the world to help elucidate disease mechanisms and in the development of new drugs. Human induced PSCs also show potential for regeneration of the myocardial tissue in experiments with small animals and in in vitro studies. Although emerging evidence points to the effectiveness of these stem cell-derived cardiomyocytes in cardiac regeneration, several challenges remain before clinical application can become a reality. Here, we provide an overview of the present state of PSC-based heart regeneration and highlight the remaining hurdles, with a particular focus on graft survival, immunogenicity, posttransplant arrhythmia, maintained function, and tumor formation. Rapid progress in this field along with advances in biotechnology are expected to resolve these issues, which will require international collaboration and standardization.

Although many studies have described the role of periostin in various diseases, the functions of periostin derived from alternative splicing and proteinase cleavage at its C-terminus remain unknown. Further experiments investigating the periostin structures that are relevant to diseases are essential for an in-depth understanding of their functions, which would accelerate their clinical applications by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress .

Heart failure caused by cardiomyocyte loss and fibrosis is a leading cause of death worldwide. Although current treatments for heart failure such as heart transplantation and left ventricular assist device implantation have obvious value, new approaches are needed. Endogenous adult cardiomyocyte renewal is measurable but inefficient and inadequate in response to extensive acute heart damage. Stimulating self-renewal of endogenous cardiomyocytes holds great promise for heart repair. Uncovering the genetic mechanisms underlying cardiomyocyte renewal is a critical step in developing new approaches to repairing the heart. Recent studies have revealed that the inhibition of the Hippo pathway is sufficient to promote the proliferation of endogenous cardiomyocytes, indicating that the manipulation of the Hippo pathway in the heart may be a promising treatment for heart failure in the future. We summarize recent findings that have shed light on the function of the Hippo pathway in heart regeneration. We also discuss the mechanisms by which Hippo pathway inhibition promotes heart regeneration and how the Hippo pathway responds to different types of injury or stress during the regenerative process. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration., (© 2018 Wiley Periodicals, Inc.)

Vertebrate organs develop through a complex process which involves interaction between multiple signaling pathways at the molecular, cell, and tissue levels. Heart development is an example of such complex process which, when disrupted, results in congenital heart disease (CHD). This complexity necessitates a holistic approach which allows the visualization of genome-wide interaction networks, as opposed to assessment of limited subsets of factors. Genomics offers a powerful solution to address the problem of biological complexity by enabling the observation of molecular processes at a genome-wide scale. The emergence of next generation sequencing (NGS) technology has facilitated the expansion of genomics, increasing its output capacity and applicability in various biological disciplines. The application of NGS in various aspects of heart biology has resulted in new discoveries, generating novel insights into this field of study. Here we review the contributions of NGS technology into the understanding of heart development and its disruption reflected in CHD and discuss how emerging NGS based methodologies can contribute to the further understanding of heart repair. [ABSTRACT FROM AUTHOR]

Heart diseases are the leading cause of death for the vast majority of people around the world, which is often due to the limited capability of human cardiac regeneration. In contrast, zebrafish have the capacity to fully regenerate their hearts after cardiac injury. Understanding and activating these mechanisms would improve health in patients suffering from long-term consequences of ischemia. Therefore, we monitored the dynamic transcriptome response of both mRNA and microRNA in zebrafish at 1⁻160 days post cryoinjury (dpi). Using a control model of sham-operated and healthy fish, we extracted the regeneration specific response and further delineated the spatio-temporal organization of regeneration processes such as cell cycle and heart function. In addition, we identified novel (miR-148/152, miR-218b and miR-19) and previously known microRNAs among the top regulators of heart regeneration by using theoretically predicted target sites and correlation of expression profiles from both mRNA and microRNA. In a cross-species effort, we validated our findings in the dynamic process of rat myoblasts differentiating into cardiomyocytes-like cells (H9c2 cell line). Concluding, we elucidated different phases of transcriptomic responses during zebrafish heart regeneration. Furthermore, microRNAs showed to be important regulators in cardiomyocyte proliferation over time.

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.

Embryonic and postnatal life depend on the uninterrupted function of cardiac muscle cells. These cells, termed cardiomyocytes, display many fascinating behaviors, including complex morphogenic movements, interactions with other cell types of the heart, persistent contractility and quiescence after birth. Each of these behaviors depends on complex interactions between both cardiac-restricted and widely expressed transcription factors, as well as on epigenetic modifications. Here, we review recent advances in our understanding of the genetic and epigenetic control of cardiomyocyte differentiation and proliferation during heart development, regeneration and disease. We focus on those regulators that are required for both heart development and disease, and highlight the regenerative principles that might be manipulated to restore function to the injured adult heart., Competing Interests: Competing interestsE.N.O. is a co-founder and member of the Scientific Advisory Board of Tenaya Therapeutics and holds equity in the company., (© 2018. Published by The Company of Biologists Ltd.)

Functional coronary circulation is essential for a healthy heart in warm-blooded vertebrates, and coronary diseases can have a fatal consequence. Despite the growing interest, the knowledge about the coronary vessel development and the roles of new coronary vessel formation during heart regeneration is still limited. It is demonstrated that early revascularization is required for efficient heart regeneration. In this comprehensive review, we first describe the coronary vessel formation from an evolutionary perspective. We further discuss the cell origins of coronary endothelial cells and perivascular cells and summarize the critical signaling pathways regulating coronary vessel development. Lastly, we focus on the current knowledge about the molecular mechanisms regulating heart regeneration in zebrafish, a genetically tractable vertebrate model with a regenerative adult heart and well-developed coronary system., Competing Interests: The authors declare no conflict of interest.