Macrophages and regeneration: Lessons from the heart

Leor, Jonathan; Palevski, Dahlia; Amit, Uri; Konfino, Tal

doi:10.1016/j.semcdb.2016.04.012

Cited by 28 publications

(22 citation statements)

References 132 publications

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“…Neonatal heart regeneration is orchestrated by multiple cell types, including cardiac resident cells and immune cells that infiltrate the heart after injury (5). Macrophages promote heart regeneration via a paracrine effect (6,7), and neural innervation has been shown to be required for neonatal heart regeneration (8). Although these studies underscore the importance of multiple cell types for neonatal heart regeneration, this process ultimately relies on the activation of CM proliferation following injury.…”

mentioning

confidence: 99%

Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

Wang

Cui

Shah

et al. 2019

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

103

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The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and nonregenerative mouse hearts over a 7-d time period following myocardial infarction injury. By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration, and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and a retained embryonic cardiogenic gene program that is active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that can be modulated to promote heart regeneration.

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mentioning

confidence: 99%

Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

Wang

Cui

Shah

et al. 2019

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

103

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“…Overactivation of the stress-related neurohormonal axis or narrowing of a coronary vessel results in an acutely diminished oxygen supply to the myocardium, which leads to necrosis, micro or macro MI, and acute inflammation, widely known as a heart attack or MI (3). As the human heart has limited regeneration capacity, restoration of the oxygen supply, in addition to infarct healing, is much dependent on the inflammatory and resolving responses, which are sterile (7). After MI, the innate inflammatory response induced by MI instigates cardiac repair processes toward either a resolving or nonresolving pathway (8).…”

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confidence: 99%

Unified nexus of macrophages and maresins in cardiac reparative mechanisms

Jadapalli

Halade

2018

FASEB j.

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Macrophages are immune-sensing "big eater" phagocytic cells responsible for an innate, adaptive, and regenerative response. After myocardial infarction, macrophages predominantly clear the deceased cardiomyocyte apoptotic or necrotic neutrophils to develop a regenerative and reparative program with the activation of the lipoxygenase-mediated maresin (MaR) metabolome at the site of ischemic injury. The specialized proresolving molecule and macrophage mediator in resolving inflammation, MaR-1, produced by human macrophages, has potent defining effects that limit polymorphonuclear neutrophil infiltration, enhance uptake of apoptotic PMNs, regulate inflammation resolution and tissue regeneration, and reduce pain. In addition to proresolving and anti-inflammatory actions, MaR-1 displays potent tissue regenerative effects in stroke and is an antinociceptive. Macrophages actively participate in the biosynthesis of bioactive MaR-2, which exhibits anti-inflammatory, proresolving, and atherosclerotic effects. A new class of macrophage-derived molecules, MaR conjugates in tissue regeneration, is identified that regulates phagocytosis and the repair and regeneration of damaged tissue. The presented review provides a current summary of the effect of MaR in resolution pathophysiology, with relevance to a cardiac repair program.-Jadapalli, J. K., Halade, G. V. Unified nexus of macrophages and maresins in cardiac reparative mechanisms.

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“…Macrophages have been suggested to play a critical role in the regeneration process, since macrophage depletion in the salamander limb impaired their ability to regenerate unless the macrophages were restored (Godwin et al 2013). Similarly, in mammals, depletion of macrophages in a neonatal myocardial infarction (MI) model impaired their heart regeneration abilities and emphasized the critical role that macrophages and monocytes play in the initial stages of regeneration Leor et al 2016). The inflammatory response following an MI in the adult heart is characterized by a biphasic wave of macrophage recruitment where M1 (Ly6 hi ) macrophages (CCR2+) accumulate and act to scavenge any debris and create a pro-inflammatory environment.…”

Section: Inflammatory Response During Cardiac Regenerationmentioning

confidence: 99%

Stimulating ideas for heart regeneration: the future of nerve-directed heart therapy

2019

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Ischemic heart disease is the leading cause of death worldwide. The blockade of coronary arteries limits oxygenrich blood to the heart and consequently there is cardiomyocyte (CM) cell death, inflammation, fibrotic scarring, and myocardial remodeling. Unfortunately, current therapeutics fail to effectively replace the lost cardiomyocytes or prevent fibrotic scarring, which results in reduced cardiac function and the development of heart failure (HF) in the adult mammalian heart. In contrast, neonatal mice are capable of regenerating their hearts following injury. However, this regenerative response is restricted to the first week of post-natal development. Recently, we identified that cholinergic nerve signaling is necessary for the neonatal mouse cardiac regenerative response. This demonstrates that cholinergic nerve stimulation holds significant potential as a bioelectronic therapeutic tool for heart disease. However, the mechanisms of nerve directed regeneration in the heart remain undetermined. In this review, we will describe the historical evidence of nerve function during regeneration across species. Specifically, we will focus on the emerging role of cholinergic innervation in modulating cardiomyocyte proliferation and inflammation during heart regeneration. Understanding the role of nerves in mammalian heart regeneration and adult cardiac remodeling can provide us with innovative bioelectronic-based therapeutic approaches for treatment of human heart disease.

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Macrophages and regeneration: Lessons from the heart

Cited by 28 publications

References 132 publications

Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

Unified nexus of macrophages and maresins in cardiac reparative mechanisms

Stimulating ideas for heart regeneration: the future of nerve-directed heart therapy

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