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Physiological Reviews Oct 2015After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of... (Review)
Review
After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world.
Topics: Animals; Cell Differentiation; Heart; Heart Diseases; Humans; Myocytes, Cardiac; Regeneration; Stem Cells
PubMed: 26269526
DOI: 10.1152/physrev.00021.2014 -
Nature Reviews. Molecular Cell Biology Aug 2013As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and... (Review)
Review
As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through 'reawakening' pathways that are active during embryogenesis. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure.
Topics: Adult; Animals; Embryonic Development; Heart; Humans; Models, Biological; Myocytes, Cardiac; Regeneration; Regenerative Medicine; Wound Healing
PubMed: 23839576
DOI: 10.1038/nrm3619 -
Circulation. Cardiovascular Genetics Oct 2017
Topics: Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Transcriptome
PubMed: 29030406
DOI: 10.1161/CIRCGENETICS.117.001950 -
Circulation Research May 2015The human heart has a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult. Instead, myocardial injury is characterized by extensive... (Review)
Review
The human heart has a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes. MicroRNAs (miRNAs), small noncoding RNAs that promote mRNA degradation and inhibit mRNA translation, have been shown to be important in cardiac development. Using this information, various researchers have used miRNAs to promote the formation of cardiomyocytes through several approaches. Several miRNAs acting in combination promote the direct conversion of cardiac fibroblasts into cardiomyocytes. Moreover, several miRNAs have been identified that aid the formation of inducible pluripotent stem cells and miRNAs also induce these cells to adopt a cardiac fate. MiRNAs have also been implicated in resident cardiac progenitor cell differentiation. In this review, we discuss the current literature as it pertains to these processes, as well as discussing the therapeutic implications of these findings.
Topics: Animals; Cell Lineage; Cell Transdifferentiation; Cellular Reprogramming; Fibroblasts; Gene Expression Regulation; Heart Diseases; Humans; MicroRNAs; Myocytes, Cardiac; Phenotype; Regeneration; Signal Transduction; Stem Cells
PubMed: 25953925
DOI: 10.1161/CIRCRESAHA.116.304377 -
International Journal of Molecular... Dec 2020ATP is a major energy source in the mammalian cells, but it is an extracellular chemical messenger acting on P2 purinergic receptors. A line of evidence has shown that... (Review)
Review
ATP is a major energy source in the mammalian cells, but it is an extracellular chemical messenger acting on P2 purinergic receptors. A line of evidence has shown that ATP is released from many different types of cells including neurons, endothelial cells, and muscle cells. In this review, we described the distribution of P2 receptor subtypes in the cardiac cells and their physiological and pathological roles in the heart. So far, the effects of external application of ATP or its analogues, and those of UTP on cardiac contractility and rhythm have been reported. In addition, specific genetic alterations and pharmacological agonists and antagonists have been adopted to discover specific roles of P2 receptor subtypes including P2X4-, P2X7-, P2Y2- and P2Y6-receptors in cardiac cells under physiological and pathological conditions. Accumulated data suggest that P2X4 receptors may play a beneficial role in cardiac muscle function, and that P2Y2- and P2Y6-receptors can induce cardiac fibrosis. Recent evidence further demonstrates P2Y1 receptor and P2X4 receptor as important mechanical signaling molecules to alter membrane potential and Ca signaling in atrial myocytes and their uneven expression profile between right and left atrium.
Topics: Adenosine Triphosphate; Animals; Biomarkers; Disease Susceptibility; Extracellular Space; Gene Expression Regulation; Heart Rate; Humans; Mechanotransduction, Cellular; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Signal Transduction; Stress, Physiological
PubMed: 33383710
DOI: 10.3390/ijms22010251 -
The Journal of Physiology Jun 2017The heart has the ability to adjust to changing mechanical loads. The Frank-Starling law and the Anrep effect describe exquisite intrinsic mechanisms the heart has for... (Review)
Review
The heart has the ability to adjust to changing mechanical loads. The Frank-Starling law and the Anrep effect describe exquisite intrinsic mechanisms the heart has for autoregulating the force of contraction to maintain cardiac output under changes of preload and afterload. Although these mechanisms have been known for more than a century, their cellular and molecular underpinnings are still debated. How does the cardiac myocyte sense changes in preload or afterload? How does the myocyte adjust its response to compensate for such changes? In cardiac myocytes Ca is a crucial regulator of contractile force and in this review we compare and contrast recent studies from different labs that address these two important questions. The 'dimensionality' of the mechanical milieu under which experiments are carried out provide important clues to the location of the mechanosensors and the kinds of mechanical forces they can sense and respond to. As a first approximation, sensors inside the myocyte appear to modulate reactive oxygen species while sensors on the cell surface appear to also modulate nitric oxide signalling; both signalling pathways affect Ca handling. Undoubtedly, further studies will add layers to this simplified picture. Clarifying the intimate links from cellular mechanics to reactive oxygen species and nitric oxide signalling and to Ca handling will deepen our understanding of the Frank-Starling law and the Anrep effect, and also provide a unified view on how arrhythmias may arise in seemingly disparate diseases that have in common altered myocyte mechanics.
Topics: Animals; Arrhythmias, Cardiac; Calcium; Humans; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Reactive Oxygen Species; Signal Transduction
PubMed: 28098356
DOI: 10.1113/JP273101 -
Journal of the American Heart... Feb 2021Cardiac fibroblasts are the primary cell type responsible for deposition of extracellular matrix in the heart, providing support to the contracting myocardium and... (Review)
Review
Cardiac fibroblasts are the primary cell type responsible for deposition of extracellular matrix in the heart, providing support to the contracting myocardium and contributing to a myriad of physiological signaling processes. Despite the importance of fibrosis in processes of wound healing, excessive fibroblast proliferation and activation can lead to pathological remodeling, driving heart failure and the onset of arrhythmias. Our understanding of the mechanisms driving the cardiac fibroblast activation and proliferation is expanding, and evidence for their direct and indirect effects on cardiac myocyte function is accumulating. In this review, we focus on the importance of the fibroblast-to-myofibroblast transition and the cross talk of cardiac fibroblasts with cardiac myocytes. We also consider the current use of models used to explore these questions.
Topics: Animals; Cells, Cultured; Fibroblasts; Heart Failure; Humans; Myocytes, Cardiac; Signal Transduction
PubMed: 33586463
DOI: 10.1161/JAHA.120.019338 -
Advances in Experimental Medicine and... 2017The spatio-temporal organization of mitochondria in cardiac myocytes facilitates myocyte-wide, cluster-bound, mitochondrial inner membrane potential oscillatory... (Review)
Review
The spatio-temporal organization of mitochondria in cardiac myocytes facilitates myocyte-wide, cluster-bound, mitochondrial inner membrane potential oscillatory depolarizations, commonly triggered by metabolic or oxidative stressors. Local intermitochondrial coupling can be mediated by reactive oxygen species (ROS) that activate inner membrane pores to initiate a ROS-induced-ROS-release process that produces synchronized limit cycle oscillations of mitochondrial clusters within the whole mitochondrial network. The network's dynamic organization, structure and function can be assessed by quantifying dynamic local coupling constants and dynamic functional clustering coefficients, both providing information about the network's response to external stimuli. In addition to its special organization, the mitochondrial network of cardiac myocytes exhibits substrate-sensitive coupling constants and clustering coefficients. The myocyte's ability to form functional clusters of synchronously oscillating mitochondria is sensitive to conditions such as substrate availability (e.g., glucose, pyruvate, β-hydroxybutyrate), antioxidant status, respiratory chain activity, or history of oxidative challenge (e.g., ischemia-reperfusion). This underscores the relevance of quantitative methods to characterize the network's functional status as a way to assess the myocyte's resilience to pathological stressors.
Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Humans; Mitochondria, Heart; Mitochondrial Dynamics; Models, Cardiovascular; Myocytes, Cardiac; Periodicity; Signal Transduction; Stochastic Processes; Time Factors
PubMed: 28551779
DOI: 10.1007/978-3-319-55330-6_1 -
Physiological Reviews Jan 2017Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a... (Review)
Review
Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a highly branched and interconnected network. Mature t-tubule networks are found in mammalian ventricular cardiomyocytes, with the transverse components of t-tubules occurring near sarcomeric z-discs. Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts.
Topics: Animals; Humans; Myocytes, Cardiac; Sarcolemma
PubMed: 27881552
DOI: 10.1152/physrev.00037.2015 -
Circulation Research Jan 2010Cardiac fibroblasts are emerging as key components of normal cardiac function, as well as the response to stressors and injury. These most numerous cells of the heart... (Review)
Review
Cardiac fibroblasts are emerging as key components of normal cardiac function, as well as the response to stressors and injury. These most numerous cells of the heart interact with myocytes via paracrine mechanisms, alterations in extracellular matrix homeostasis, and direct cell-cell interactions. It is possible that they are a contributor to the inability of adult myocytes to proliferate and may influence cardiac progenitor biology. Furthering our understanding of how cardiac fibroblasts and myocytes interact may provide an avenue to novel treatments for heart failure prevention. This review discusses the most recent concepts in cardiac fibroblast-myocyte communication and areas of potential future research.
Topics: Animals; Cell Proliferation; Extracellular Matrix; Fibroblasts; Heart Failure; Humans; Myocytes, Cardiac; Paracrine Communication
PubMed: 20056945
DOI: 10.1161/CIRCRESAHA.109.207456