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At least 19 recordsLinked to original sources
PubMed2006

Gene expression analysis of zebrafish heart regeneration.

Mammalian hearts cannot regenerate. In contrast, zebrafish hearts regenerate even when up to 20% of the ventricle is amputated. The mechanism of zebrafish heart regeneration is not understood. To systematically characterize this process at the molecular level, we generated transcriptional profiles of zebrafish cardiac regeneration by microarray analyses. Distinct gene clusters were identified based on temporal expression patterns. Genes coding for wound response/inflammatory factors, secreted molecules, and matrix metalloproteinases are expressed in regenerating heart in sequential patterns. Comparisons of gene expression profiles between heart and fin regeneration revealed a set of regeneration core molecules as well as tissue-specific factors. The expression patterns of several secreted molecules around the wound suggest that they play important roles in heart regeneration. We found that both platelet-derived growth factor-a and -b (pdgf-a and pdgf-b) are upregulated in regenerating zebrafish hearts. PDGF-B homodimers induce DNA synthesis in adult zebrafish cardiomyocytes. In addition, we demonstrate that a chemical inhibitor of PDGF receptor decreases DNA synthesis of cardiomyocytes both in vitro and in vivo during regeneration. Our data indicate that zebrafish heart regeneration is associated with sequentially upregulated wound healing genes and growth factors and suggest that PDGF signaling is required.

Animals↗
PubMed2002

Heart regeneration in zebrafish.

Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. The hearts of zebrafish with mutations in the Mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars. Thus, injury-induced cardiomyocyte proliferation in zebrafish can overcome scar formation, allowing cardiac muscle regeneration. These findings indicate that zebrafish will be useful for genetically dissecting the molecular mechanisms of cardiac regeneration.

Animals↗
PubMed2003

Activation of Notch signaling pathway precedes heart regeneration in zebrafish.

Several vertebrates display the ability to regenerate parts of their body after amputation. During this process, differentiated cells reenter the cell cycle and proliferate to generate a mass of undifferentiated cells. Repatterning mechanisms act on these cells to eventually shape a regenerated tissue or organ that replaces the amputated one. Experiments with regenerating limbs/fins in newts and zebrafish have shown that members of the Msx family of homeodomain-containing transcription factors play key roles during blastema formation and patterning. Here we show that adult zebrafish have a remarkable capacity to regenerate the heart in a process that involves up-regulation of msxB and msxC genes. We present evidence indicating that heart regeneration involves the execution of a specific genetic program, rather than redeployment of a cardiac development program. Preceding Msx activation, there is a marked increase in the expression of notch1b and deltaC, which we show are also up-regulated during fin regeneration. These data suggest a role for the Notch pathway in the activation of the regenerative response. Taken together, our results underscore the use of zebrafish as a model for investigating the process of regeneration in particular and the biology of stem cells in general. Advances in these fields will undoubtedly aid in the implementation of strategies for regenerative medicine.

Animals↗
PubMed2004

The zebrafish as a model of heart regeneration.

Regeneration is a complex biological process by which animals can restore the shape, structure and function of body parts lost after injury, or after experimental amputation. Only a few species of vertebrates display the capacity to regenerate body parts during adulthood. In the case of the heart, newts display a remarkable ability to regenerate large portions of myocardium after amputation, although the mechanisms underlying this process have not been addressed. Recently, it has been shown that adult zebrafish can also regenerate their hearts, thus offering new possibilities for experimentally approaching this fascinating biological phenomenon. The first insights into heart regeneration gained by studying this model organism are reviewed here.

Animals↗
PubMed2005

Ponce de Leon's Fountain: stem cells and the regenerating heart.

Despite current pharmacologic and whole organ transplantation strategies, advanced heart failure remains a common and deadly disease. Limited availability of donor organs for use in orthotopic heart transplantation has prompted the examination of alternative therapies, including cell transfer strategies. Stem cell populations have been identified in virtually all postnatal tissues with the exception of the heart, and these stem cells function in the maintenance and regeneration of the respective tissues. Recent studies challenge preexisting notions regarding cardiac repair and suggest that the heart is capable of limited regeneration through the activation of resident cardiac stem cells or the recruitment of stem cell populations from other tissues such as the bone marrow. This review highlights animal models that have the capacity for myocardial regeneration and examines potential sources of stem cell populations that may participate in tissue regeneration. While some authors view these cell-based strategies as a Fountain of Youth for the myopathic heart, future studies will decipher the regulatory mechanisms of stem cell populations and serve as a prelude to stem cell-based strategies.

Animals↗
PubMed2006

A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration.

Zebrafish possess a unique yet poorly understood capacity for cardiac regeneration. Here, we show that regeneration proceeds through two coordinated stages following resection of the ventricular apex. First a blastema is formed, comprised of progenitor cells that express precardiac markers, undergo differentiation, and proliferate. Second, epicardial tissue surrounding both cardiac chambers induces developmental markers and rapidly expands, creating a new epithelial cover for the exposed myocardium. A subpopulation of these epicardial cells undergoes epithelial-to-mesenchymal transition (EMT), invades the wound, and provides new vasculature to regenerating muscle. During regeneration, the ligand fgf17b is induced in myocardium, while receptors fgfr2 and fgfr4 are induced in adjacent epicardial-derived cells. When fibroblast growth factors (Fgf) signaling is experimentally blocked by expression of a dominant-negative Fgf receptor, epicardial EMT and coronary neovascularization fail, prematurely arresting regeneration. Our findings reveal injury responses by myocardial and epicardial tissues that collaborate in an Fgf-dependent manner to achieve cardiac regeneration.

Animals↗
PubMed2001

Heart regeneration in adult MRL mice.

The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signaling, extracellular matrix remodeling, and compensatory adaptation of myocytes. Myocardial regeneration is observed in amphibians, whereas scar formation characterizes cardiac ventricular wound healing in a variety of mammalian injury models. We have previously shown that the MRL mouse strain has an extraordinary capacity to heal surgical wounds, a complex trait that maps to at least seven genetic loci. Here, we extend these studies to cardiac wounds and demonstrate that a severe transmural, cryogenically induced infarction of the right ventricle heals extensively within 60 days, with the restoration of normal myocardium and function. Scarring is markedly reduced in MRL mice compared with C57BL/6 mice, consistent with both the reduced hydroxyproline levels seen after injury and an elevated cardiomyocyte mitotic index of 10-20% for the MRL compared with 1-3% for the C57BL/6. The myocardial response to injury observed in these mice resembles the regenerative process seen in amphibians.

Animals↗
PubMed2005

Heart valve regeneration.

The valves of the heart cannot regenerate spontaneously. Therefore, heart valve disease generally necessitates surgical repair or replacement of the diseased tissue by mechanical or bioprosthetic valve substitutes in order to avoid potentially fatal cardiac or systemic consequences. Although survival and quality of life is enhanced for many patients treated surgically, currently available valve substitutes remain imperfect. This is especially the case in pediatric applications, where physiologically corrective procedures can be successfully performed, but reoperations are frequently required to replace failed valve substitutes or accommodate growth of the patient. While much work is currently underway to incrementally improve existing valve substitutes, a major impact will require radically new technologies, including tissue engineering or regeneration. The use of engineered tissue offers the potential to create a non-obstructive, non-thrombogenic tissue valve substitute containing living cells capable of providing ongoing remodeling and repair of cumulative injury to the extracellular matrix. Ideally, this would allow growth in maturing recipients. The innovative fabrication of materials and the development of sophisticated methods to repair or regenerate damaged or diseased heart valves requires integration of a diverse array of basic scientific principles and enabling technologies. Thus, heart valve tissue engineering requires an understanding of relationships of structure to function in normal and pathological valves (including mechanisms of embryological development, tissue repair and functional biomechanics), and the ability to control cell and tissue responses to injury, physical stimuli and biomaterial surfaces, through chemical, pharmacological, mechanical and potentially genetic manipulations. These approaches created by advances in cell biology raise exciting possibilities for in situ regeneration and repair of heart valves.

Bioprosthesis↗
PubMed2006

The HeArt of regeneration.

Fish and amphibian hearts are known to regenerate after partial resection, but the molecular mechanisms underlying this process remain unclear. In this issue of Cell, Lipilina et al. analyze regeneration in the zebrafish heart. Their work indicates that new cardiomyocytes originate from undifferentiated progenitor cells and reveals a critical role for the epicardium, the cellular layer that covers the heart.

Animals↗
PubMed2004

Engineered heart tissue for regeneration of diseased hearts.

Cardiac tissue engineering aims at providing contractile heart muscle constructs for replacement therapy in vivo. At present, most cardiac tissue engineering attempts utilize heart cells from embryonic chicken and neonatal rats and scaffold materials. Over the past years our group has developed a novel technique to engineer collagen/matrigel-based cardiac muscle constructs, which we termed engineered heart tissue (EHT). EHT display functional and morphological properties of differentiated heart muscle and can be constructed in different shape and size from collagen type I, extracellular matrix proteins (Matrigel((R))), and heart cells from neonatal rats and embryonic chicken. First implantation studies in syngeneic Fischer 344 rats provided evidence of EHT survival and integration in vivo. This review will focus on our experience in tissue engineering of cardiac muscle. Mainly, EHT construction, matrix requirements, potential applications of different cell types including stem cells, and our first implantation experiences will be discussed. Despite many critical and unresolved questions, we believe that cardiac tissue engineering in general has an interesting perspective for the replacement of malfunctioning myocardium and reconstruction of congenital malformations.

Animals↗
PubMed2006

[Regenerative therapy for damaged heart].

Regeneration therapy has currently emerged as one of the promising treatments for the patients suffering from severe heart dysfunction. Direct transplantation of isolated myoblasts or bone marrow mononuclear cells, and recruitment of stem cells from bone marrow by G-CSF administration have been already clinically performed. As further advanced therapy, research on fabricating three-dimensional (3-D) cardiac grafts by tissue engineering technology has also now begun. Most popular approach of tissue engineering is using 3-D biodegradable scaffolds as alternatives of extracellular matrix. By contrast, we have successfully fabricated macroscopically beating myocardial tissue by layering cell sheets which are harvested from intelligent culture dishes grafted with temperature-responsive polymer in nano-scale. These regenerative medicines should rescue many patients.

Animals↗
PubMed2006

[Stem cell therapy for the regeneration of heart muscle].

The loss of contractile heart tissue - often a sequelae of cardiac infarction - is caused by the limited regeneration capacity of the heart and usually leads to irreversible organ damage. Modification of this regeneration capacity by cell-based cardiac therapies with precursor and stem cells opens a new therapeutic field. A number of different (stem)cell types and applications are currently being evaluated. The possibilities and risks of the therapy are not easily foreseeable, however, clinical applications are already visible. In the light of stem cell research, the vision of regrowth of the heart in analogy to the Prometheus saga is obtaining a scientific explanation and may lead to new cardiac therapies.

Bone Marrow Transplantation↗
PubMed2006

Regenerating the heart using human embryonic stem cells--from cell to bedside.

The adult human heart has limited regenerative capacity and, therefore, functional restoration of the damaged heart presents a great challenge. Despite the progress achieved in the pharmacological and surgical treatment of degenerative myocardial diseases, they are still considered a major cause of morbidity and mortality in the western world. Repopulation of the damaged heart with cardiomyocytes represents a novel conceptual therapeutic paradigm but is hampered by the lack of sources for human cardiomyocytes. The recent derivation of pluripotent human embryonic stem cell lines may provide a solution for this cell sourcing problem. This review will focus on the derivation of the hESC lines, their mechanism of self-renewal, and their differentiation to cardiomyocytes. The possible signals and cues involved in the commitment and early differentiation of cardiomyocytes in this model will be discussed as well as the molecular, structural and electrophysiologic characteristics of the generated hESC-derived cardiomyocytes. Finally, the hurdles and challenges toward fully harnessing the potential clinical applications of these unique cells will be described.

Animals↗
PubMed2006

Getting to the heart of regeneration in zebrafish.

A scientific and clinical prerogative of the 21st century is to stimulate the regenerative ability of the human heart. While the mammalian heart shows little or no natural regeneration in response to injury, certain non-mammalian vertebrates possess an elevated capacity for cardiac regeneration. Adult zebrafish restore ventricular muscle removed by surgical resection, events that involve little or no scarring. Recent studies have begun to reveal cellular and molecular mechanisms of this regenerative process that have exciting implications for human cardiac biology and disease.

Amphibians↗
PubMed2003

Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes.

Adult newt cardiomyocytes, in contrast to their mammalian counterparts, can proliferate after injury and contribute to the functional regeneration of the heart. In order to understand the mechanisms underlying this plasticity we performed longitudinal studies on single cardiomyocytes in culture. We find that the majority of cardiomyocytes can enter S phase, a process that occurs in response to serum-activated pathways and is dependent on the phosphorylation of the retinoblastoma protein. However, more than half of these cells stably arrest at either entry to mitosis or during cytokinesis, thus resembling the behaviour observed in mammalian cardiomyocytes. Approximately a third of the cells progress through mitosis and may enter successive cell divisions. When cardiomyocytes divided more than once, the proliferative behaviour of sister cells was significantly correlated, in terms of whether they underwent a subsequent cell cycle, and if so, the duration of that cycle. These observations suggest a mechanism whereby newt heart regeneration depends on the retention of proliferative potential in a subset of cardiomyocytes. The regulation of the remaining newt cardiomyocytes is similar to that described for their mammalian counterparts, as they arrest during mitosis or cytokinesis. Understanding the nature of this block and why it arises in some but not other newt cardiomyocytes may lead to an augmentation of the regenerative potential in the mammalian heart.

Animals↗