scholarly journals Vertebrate cardiac regeneration: evolutionary and developmental perspectives

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Stephen Cutie ◽  
Guo N. Huang
Keyword(s):  
Cardiac Injury ◽  
Adaptive Immune System ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Adaptive Immune ◽  
Selective Pressures ◽  
Trade Offs ◽  
Lower Vertebrates ◽  
Complex Adaptive ◽  
And Function

AbstractCardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures, and as members of certain species developmentally progress towards their adult forms. While higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults, neonates of these same species can fully regenerate heart structure and function after injury – as can adult lower vertebrates like many teleost fish and urodele amphibians. Recent research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally: an oxygen-rich environment, vertebrate thermogenesis, a complex adaptive immune system, and cancer risk trade-offs. In this review, we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.

scholarly journals The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

2021 ◽  
Vol 22 (15) ◽  
pp. 7923
Author(s):  
Santiago Alvarez-Argote ◽  
Caitlin C. O’Meara
Keyword(s):  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Normal Function ◽  
Cardiac Conduction ◽  
Cell Detection ◽  
Fate Mapping ◽  
The Novel ◽  
Functional Roles ◽  
Macrophage Populations ◽  
And Function

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

scholarly journals Decoding an organ regeneration switch by dissecting cardiac regeneration enhancers

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev194019
Author(s):  
Ian J. Begeman ◽  
Kwangdeok Shin ◽  
Daniel Osorio-Méndez ◽  
Andrew Kurth ◽  
Nutishia Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Regeneration ◽  
Cardiac Injury ◽  
Transcriptional Response ◽  
Cardiac Regeneration ◽  
Regulatory Elements ◽  
Heart Regeneration ◽  
New Paradigm ◽  
Closely Related Species ◽  
Organ Regeneration

ABSTRACTHeart regeneration in regeneration-competent organisms can be accomplished through the remodeling of gene expression in response to cardiac injury. This dynamic transcriptional response relies on the activities of tissue regeneration enhancer elements (TREEs); however, the mechanisms underlying TREEs are poorly understood. We dissected a cardiac regeneration enhancer in zebrafish to elucidate the mechanisms governing spatiotemporal gene expression during heart regeneration. Cardiac lepb regeneration enhancer (cLEN) exhibits dynamic, regeneration-dependent activity in the heart. We found that multiple injury-activated regulatory elements are distributed throughout the enhancer region. This analysis also revealed that cardiac regeneration enhancers are not only activated by injury, but surprisingly, they are also actively repressed in the absence of injury. Our data identified a short (22 bp) DNA element containing a key repressive element. Comparative analysis across Danio species indicated that the repressive element is conserved in closely related species. The repression mechanism is not operational during embryogenesis and emerges when the heart begins to mature. Incorporating both activation and repression components into the mechanism of tissue regeneration constitutes a new paradigm that might be extrapolated to other regeneration scenarios.

scholarly journals Optimizing Dendritic Cell-Based Immunotherapy: Tackling the Complexity of Different Arms of the Immune System

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Ilse Van Brussel ◽  
Zwi N. Berneman ◽  
Nathalie Cools
Keyword(s):  
Immune System ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Cellular Mechanisms ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
New Ideas ◽  
And Function

Earlier investigations have revealed a surprising complexity and variety in the range of interaction between cells of the innate and adaptive immune system. Our understanding of the specialized roles of dendritic cell (DC) subsets in innate and adaptive immune responses has been significantly advanced over the years. Because of their immunoregulatory capacities and because very small numbers of activated DC are highly efficient at generating immune responses against antigens, DCs have been vigorously used in clinical trials in order to elicit or amplify immune responses against cancer and chronic infectious diseases. A better insight in DC immunobiology and function has stimulated many new ideas regarding the potential ways forward to improve DC therapy in a more fundamental way. Here, we discuss the continuous search for optimal in vitro conditions in order to generate clinical-grade DC with a potent immunogenic potential. For this, we explore the molecular and cellular mechanisms underlying adequate immune responses and focus on most favourable DC culture regimens and activation stimuli in humans. We envisage that by combining each of the features outlined in the current paper into a unified strategy, DC-based vaccines may advance to a higher level of effectiveness.

scholarly journals Myocardial NF-κB activation is essential for zebrafish heart regeneration

2015 ◽  
Vol 112 (43) ◽  
pp. 13255-13260 ◽  
Author(s):  
Ravi Karra ◽  
Anne K. Knecht ◽  
Kazu Kikuchi ◽  
Kenneth D. Poss
Keyword(s):  
Tissue Regeneration ◽  
Therapeutic Strategy ◽  
Cardiac Injury ◽  
Regulatory Sequences ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Developmental Program ◽  
Lower Vertebrates ◽  
Outstanding Question ◽  
Zebrafish Heart

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.

scholarly journals Development of Immunopathobiogenesis on SIRS-Sepsis

2009 ◽  
Vol 1 (1) ◽  
pp. 32
Author(s):  
A Guntur Hermawan
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Proinflammatory Cytokines ◽  
Critical Role ◽  
Adaptive Immune System ◽  
Multiple Organ ◽  
Toxic Shock ◽  
Sepsis Diagnosis ◽  
Adaptive Immune ◽  
And Function

Over the past decade, sepsis has been diagnosed according to consensus guidelines established in 1991 as an infection in addition to the symptoms of systemic inflammatory response syndrome (SIRS). In addition to the previous criteria, the 2001 conference added several new diagnostic criteria for sepsis. Of particular interest was the inclusion of the biomarkers procalcitonin (PCT) and C-reactive protein (CRP), despite the overall conclusion that it was premature to use biomarkers for sepsis diagnosis. The primary recommendation of the panel was the implementation of the Predisposition, insult Infection, Response, and Organ dysfunction (PIRO).The immune system has traditionally been devided into innate and adaptive components, each of which has a different role and function in defending the host against infectious agents. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also increasing evidence supports an additional critical role for TLRs in orchestrating the development of adaptive immune responses.The superantigens are able to induce toxic shock syndrome and can sometimes cause multiple organ failure via adaptive immune system. The superantigenic activity of the bacterial exotoxins can be attributed to their ability to cross-link major histocompatibility complex class II molecules on antigen-presenting cells outside the peptide groove with T-cell receptors to form a trimolecular complex. This trimolecular interaction leads to uncontrolled release of a number of proinflammatory cytokines. Proinflammatory cytokines especially IFN-γ and TNF-α, the key cytokines causing toxic shock syndrome.KEYWORDS: sepsis, innate immunity, adaptive

scholarly journals Genetic Diversity of Toll-Like Receptors and Immunity toM. lepraeInfection

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Bryan E. Hart ◽  
Richard I. Tapping
Keyword(s):  
Association Studies ◽  
Genetic Association Studies ◽  
Adaptive Immune System ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Genetic Associations ◽  
Toll Like Receptors ◽  
Adaptive Immune ◽  
Polymorphic Variants ◽  
And Function

Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection withMycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity.

scholarly journals Immunomodulation for optimal cardiac regeneration: insights from comparative analyses

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Luiza Farache Trajano ◽  
Nicola Smart
Keyword(s):  
Human Heart ◽  
Tissue Injury ◽  
Adaptive Immune System ◽  
Cardiac Regeneration ◽  
Sterile Inflammation ◽  
Cardiac Damage ◽  
Physical Trauma ◽  
Adaptive Immune ◽  
Immune Mediated ◽  
Regenerative Therapies

AbstractDespite decades of research, regeneration of the infarcted human heart remains an unmet ambition. A significant obstacle facing experimental regenerative therapies is the hostile immune response which arises following a myocardial infarction (MI). Upon cardiac damage, sterile inflammation commences via the release of pro-inflammatory meditators, leading to the migration of neutrophils, eosinophils and monocytes, as well as the activation of local vascular cells and fibroblasts. This response is amplified by components of the adaptive immune system. Moreover, the physical trauma of the infarction and immune-mediated tissue injury provides a supply of autoantigens, perpetuating a cycle of autoreactivity, which further contributes to adverse remodelling. A gradual shift towards an immune-resolving environment follows, culminating in the formation of a collagenous scar, which compromises cardiac function, ultimately driving the development of heart failure. Comparing the human heart with those of animal models that are capable of cardiac regeneration reveals key differences in the innate and adaptive immune responses to MI. By modulating key immune components to better resemble those of regenerative species, a cardiac environment may be established which would, either independently or via the synergistic application of emerging regenerative therapies, improve functional recovery post-MI.

Abstract 17364: G-protein Signaling Regulation of the Hippo Pathway in Neonatal Heart Regeneration

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masahide Sakabe ◽  
Aishlin Hassan ◽  
Mei Xin
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Adult Age ◽  
Rhoa Activity ◽  
Β Blocker

Introduction: The regeneration potential in the adult mammalian heart is very limited due to the cessation of cardiomyocyte proliferation shortly after birth. Recent studies have revealed that changes after birth such as metabolic state, oxygen level, cardiomyocyte structure and maturity, immune system and polyploidy are among the factors contributing to the loss of the regenerative potential in the heart. The mechanisms that regulate the cardiac regenerative window are not well understood. Here we report that G-protein mediated signaling regulates Hippo-YAP in neonatal cardiomyocyte proliferation and heart regeneration through Rho activity. Hypothesis: Gas encoded by the Gnas gene, a downstream effector of beta-adrenergic receptor (βAR) inhibits cardiomyocyte proliferation via regulation of YAP activity. Methods: We pharmacologically inhibited the G protein coupled receptor mediated β adrenergic signaling with a β-blocker (metoprolol) at early postnatal stages, and genetically by deleting Gnas in the heart with αMHC-Cre. We accessed the cardiomyocyte proliferation, heart regeneration in these mice and elucidated molecular mechanisms. Results: We found that β-blocker enhanced cardiomyocyte proliferation and promoted cardiac regeneration post cardiac injury with improved cardiac function. Consistent with β-blocker treated mice, mice lacking Gnas in cardiomyocytes exhibited enlarged hearts with an increase in cardiomyocyte proliferation. RNA-seq analysis revealed that these cardiomyocytes maintained an immature status even at young-adult age. The genes associated with mitochondrial oxidative metabolism, the major energy source for mature cardiomyocytes, were downregulated. Moreover, YAP activity was upregulated in both cases. We also found that loss of Gαs function caused upregulation of RhoA activity, and inhibitor of Rho signaling pathway suppressed the YAP activity in cardiomyocytes. Conclusions: Our study reveals that Gαs negatively regulate cardiomyocyte proliferation and provides mechanistic insight for β-blocker treatment as a strategy for inducing cardiac dedifferentiation and proliferation in injured heart.

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