scholarly journals Polyploid cardiomyocytes: implications for heart regeneration

Development ◽  
2021 ◽  
Vol 148 (14) ◽  
Author(s):  
Anna Kirillova ◽  
Lu Han ◽  
Honghai Liu ◽  
Bernhard Kühn
Keyword(s):  
Cellular Proliferation ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Form And Function ◽  
Differentiated Cells ◽  
New Findings ◽  
Polyploid Cells ◽  
And Function

ABSTRACT Terminally differentiated cells are generally thought to have arrived at their final form and function. Many terminally differentiated cell types are polyploid, i.e. they have multiple copies of the normally diploid genome. Mammalian heart muscle cells, termed cardiomyocytes, are one such example of polyploid cells. Terminally differentiated cardiomyocytes are bi- or multi-nucleated, or have polyploid nuclei. Recent mechanistic studies of polyploid cardiomyocytes indicate that they can limit cellular proliferation and, hence, heart regeneration. In this short Spotlight, we present the mechanisms generating bi- and multi-nucleated cardiomyocytes, and the mechanisms generating polyploid nuclei. Our aim is to develop hypotheses about how these mechanisms might relate to cardiomyocyte proliferation and cardiac regeneration. We also discuss how these new findings could be applied to advance cardiac regeneration research, and how they relate to studies of other polyploid cells, such as cancer cells.

Abstract 225: Coordinated Transcriptome and Cell State Dynamics of Non-myocytes in Heart Regeneration

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Hong Ma ◽  
Ziqing Liu ◽  
Yuchen Yang ◽  
Dong Feng ◽  
Yanhan Dong ◽  
...  
Keyword(s):  
Cardiac Regeneration ◽  
Cell Types ◽  
Multiple Time ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cellular Functions ◽  
Molecular Features ◽  
Functional Dynamics ◽  
Cell Diversity ◽  
Multiple Time Points

Cardiac regeneration occurs primarily through proliferation of existing cardiomyocytes, yet the regenerative response also involves complex interactions between distinct cardiac cell types including not only cardiomyocytes, but also non-cardiomyocytes (nonCMs). However, the subpopulations, distinguishing molecular features, cellular functions, and intercellular interactions of nonCMs in heart regeneration remain largely unexplored. Using the LIGER algorithm, we assembled an atlas of cell states from 61,977 individual nonCM scRNA-seq profiles isolated at multiple time points during heart regeneration in both wildtype and mutant fish. This analysis revealed extensive nonCM cell diversity, including multiple macrophage, fibroblast and endothelial subpopulations with unique spatiotemporal distributions and cooperative interactions during the process of cardiac regeneration. Genetic and pharmacological perturbation of macrophage functional dynamics compromised interactions among nonCM subpopulations, reduced cardiomyocyte proliferation, and caused defective cardiac regeneration. Furthermore, we developed a computational algorithm called Topologizer to map the topological relationships and dynamics of nonCMs during heart regeneration. We uncovered dynamic transitions between macrophage functional states and identified factors involved in mRNA processing and transcriptional regulation associated with the transition. Together, our single-cell transcriptomic analysis of nonCMs during cardiac regeneration provides a blueprint for interrogating the molecular and cellular basis of cardiac regeneration.

scholarly journals Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

2020 ◽  
Author(s):  
Rebecca Ryan ◽  
Bethany R. Moyse ◽  
Rebecca J. Richardson
Keyword(s):  
Cardiac Injury ◽  
Cell Communication ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Regenerative Process ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Underlying Mechanisms ◽  
Different Cell Types

Abstract The study of heart repair post-myocardial infarction has historically focused on the importance of cardiomyocyte proliferation as the major factor limiting adult mammalian heart regeneration. However, there is mounting evidence that a narrow focus on this one cell type discounts the importance of a complex cascade of cell–cell communication involving a whole host of different cell types. A major difficulty in the study of heart regeneration is the rarity of this process in adult animals, meaning a mammalian template for how this can be achieved is lacking. Here, we review the adult zebrafish as an ideal and unique model in which to study the underlying mechanisms and cell types required to attain complete heart regeneration following cardiac injury. We provide an introduction to the role of the cardiac microenvironment in the complex regenerative process and discuss some of the key advances using this in vivo vertebrate model that have recently increased our understanding of the vital roles of multiple different cell types. Due to the sheer number of exciting studies describing new and unexpected roles for inflammatory cell populations in cardiac regeneration, this review will pay particular attention to these important microenvironment participants.

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 Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ugochukwu Kelvin Ihenacho ◽  
Kelsey A. Meacham ◽  
Megan Cleland Harwig ◽  
Michael E. Widlansky ◽  
R. Blake Hill
Keyword(s):  
Human Health ◽  
Neurological Disorders ◽  
Mitochondrial Fission ◽  
Cell Types ◽  
Mitochondrial Division ◽  
Form And Function ◽  
Health And Disease ◽  
Genetic Deletion ◽  
And Function

Mitochondrial fission protein 1 (Fis1) was identified in yeast as being essential for mitochondrial division or fission and subsequently determined to mediate human mitochondrial and peroxisomal fission. Yet, its exact functions in humans, especially in regard to mitochondrial fission, remains an enigma as genetic deletion of Fis1 elongates mitochondria in some cell types, but not others. Fis1 has also been identified as an important component of apoptotic and mitophagic pathways suggesting the protein may have multiple, essential roles. This review presents current perspectives on the emerging functions of Fis1 and their implications in human health and diseases, with an emphasis on Fis1’s role in both endocrine and neurological disorders.

Form and Function in Cells of the Brain

The Neuron ◽  
2015 ◽  
pp. 23-38
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Axonal Transport ◽  
Molecular Motors ◽  
Critical Role ◽  
Neuronal Cell ◽  
Cell Types ◽  
Neuronal Cell Body ◽  
Long Distance ◽  
Form And Function ◽  
And Function ◽  
The Brain

This chapter examines unique mechanisms that the neuron has evolved to establish and maintain the form required for its specialized signaling functions. Unlike some other organs, the brain contains a variety of cell types including several classes of glial cells, which play a critical role in the formation of the myelin sheath around axons and may be involved in immune responses, synaptic transmission, and long-distance calcium signaling in the brain. Neurons share many features in common with other cells (including glia), but they are distinguished by their highly asymmetrical shapes. The neuronal cytoskeleton is essential for establishing this cell shape during development and for maintaining it in adulthood. The process of axonal transport moves vesicles and other organelles to regions remote from the neuronal cell body. Proteins such as kinesin and dynein, called molecular motors, make use of the energy released by hydrolysis of ATP to drive axonal transport.

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

2019 ◽  
Vol 116 (37) ◽  
pp. 18455-18465 ◽  
Author(s):  
Zhaoning Wang ◽  
Miao Cui ◽  
Akansha M. Shah ◽  
Wenduo Ye ◽  
Wei Tan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rna Binding ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cardiac Regeneration ◽  
Later Life ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Neonatal Heart ◽  
Short Period

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.

Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations

2015 ◽  
Vol 309 (8) ◽  
pp. H1237-H1250 ◽  
Author(s):  
Marina Leone ◽  
Ajit Magadum ◽  
Felix B. Engel
Keyword(s):  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Cardiac Regeneration ◽  
Experimental Medicine ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Naturally Occurring ◽  
Ability To Regenerate ◽  
Zebrafish Heart

The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.

scholarly journals Molecular regulation of myocardial proliferation and regeneration

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Lixia Zheng ◽  
Jianyong Du ◽  
Zihao Wang ◽  
Qinchao Zhou ◽  
Xiaojun Zhu ◽  
...  
Keyword(s):  
Recent Literature ◽  
Biological Process ◽  
Cardiac Regeneration ◽  
Molecular Regulation ◽  
Mouse Heart ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cellular Mechanisms ◽  
Concise Review ◽  
Complex Biological Process

AbstractHeart regeneration is a fascinating and complex biological process. Decades of intensive studies have revealed a sophisticated molecular network regulating cardiac regeneration in the zebrafish and neonatal mouse heart. Here, we review both the classical and recent literature on the molecular and cellular mechanisms underlying heart regeneration, with a particular focus on how injury triggers the cell-cycle re-entry of quiescent cardiomyocytes to replenish their massive loss after myocardial infarction or ventricular resection. We highlight several important signaling pathways for cardiomyocyte proliferation and propose a working model of how these injury-induced signals promote cardiomyocyte proliferation. Thus, this concise review provides up-to-date research progresses on heart regeneration for investigators in the field of regeneration biology.

scholarly journals Hormonal control of cardiac regenerative potential

2020 ◽  
Author(s):  
Alexander V. Amram ◽  
Stephen Cutie ◽  
Guo N. Huang
Keyword(s):  
Vitamin D ◽  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Cardiac Regeneration ◽  
Postnatal Period ◽  
Hormonal Control ◽  
Model Systems ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Endocrine Signaling

Research conducted across phylogeny on cardiac regenerative responses following heart injury implicates endocrine signaling as a pivotal regulator of both cardiomyocyte proliferation and heart regeneration. Three prominently studied endocrine factors are thyroid hormone, vitamin D, and glucocorticoids, which canonically regulate gene expression through their respective nuclear receptors thyroid hormone receptor, vitamin D receptor, and glucocorticoid receptor. The main animal model systems of interest include humans, mice, and zebrafish, which vary in cardiac regenerative responses possibly due to the differential onsets and intensities of endocrine signaling levels throughout their embryonic to postnatal organismal development. Zebrafish and lower vertebrates tend to retain robust cardiac regenerative capacity into adulthood while mice and other higher vertebrates experience greatly diminished cardiac regenerative potential in their initial postnatal period that is sustained throughout adulthood. Here, we review recent progress in understanding how these three endocrine signaling pathways regulate cardiomyocyte proliferation and heart regeneration with a particular focus on the controversial findings that may arise from different assays, cellular-context, age, and species. Further investigating the role of each endocrine nuclear receptor in cardiac regeneration from an evolutionary perspective enables comparative studies between species in hopes of extrapolating the findings to novel therapies for human cardiovascular disease.

scholarly journals Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
T. Bradley Willingham ◽  
Peter T. Ajayi ◽  
Brian Glancy
Keyword(s):  
Skeletal Muscle ◽  
Energy Homeostasis ◽  
Single Cells ◽  
Muscle Cells ◽  
Cell Types ◽  
Current Data ◽  
Skeletal Muscle Cells ◽  
Form And Function ◽  
Mitochondrial Heterogeneity ◽  
And Function

Across different cell types and within single cells, mitochondria are heterogeneous in form and function. In skeletal muscle cells, morphologically and functionally distinct subpopulations of mitochondria have been identified, but the mechanisms by which the subcellular specialization of mitochondria contributes to energy homeostasis in working muscles remains unclear. Here, we discuss the current data regarding mitochondrial heterogeneity in skeletal muscle cells and highlight potential new lines of inquiry that have emerged due to advancements in cellular imaging technologies.

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