Proximity to injury, but neither number of nuclei nor ploidy define pathological adaptation and plasticity in cardiomyocytes

Hesse, Michael; Bednarz, Ralf; Carls, E.; Becker, Cora; Bondareva, Olga; Lother, Achim; Geisen, Caroline; Dreßen, Martina; Krane, Markus; Roell, Wilhelm; Hein, Lutz; Fleischmann, Bernd K.; Gilsbach, Ralf

doi:10.1016/j.yjmcc.2020.11.012

Cited by 13 publications

(20 citation statements)

References 35 publications

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“…Although one report showed that all adult mouse cardiomyocytes have a largely uniform transcriptional profile (Yekelchyk et al, 2019), another group reported differences as a result of Ect2 gene inactivation-induced cytokinesis failure (Windmueller et al, 2020). A recently published study identified that the transcriptional profile of cardiomyocytes is independent of ploidy or nucleation but only differs in response to injury (Hesse et al, 2021). It is possible that many currently used techniques for single-cell transcriptional profiling do not capture the genome-wide transcriptome of single cells and thus do not have the sufficient depth to reveal all differences at the single cell level, highlighting that further studies are needed.…”

Section: Discussionmentioning

confidence: 99%

Polyploid cardiomyocytes: implications for heart regeneration

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Polyploid cardiomyocytes: implications for heart regeneration

et al. 2021

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“…Novel methodologies that provide deeper Insights into the local molecular mechanisms will open new perspectives. While physiological measurements at the single cell level are commonplace, only recently have we begun to understand the transcriptomic changes and their underlying regulatory mechanisms in BZ remodelling [211,212]. Transcriptomes generated from tissue is compromised by the mixture of cell types present, which through changes in cell type abundance may mask alterations in gene expression in individual cell types [211].…”

Section: Systemic Small Molecule Therapy or Local Bz Targeted Therapymentioning

confidence: 99%

“…While physiological measurements at the single cell level are commonplace, only recently have we begun to understand the transcriptomic changes and their underlying regulatory mechanisms in BZ remodelling [211,212]. Transcriptomes generated from tissue is compromised by the mixture of cell types present, which through changes in cell type abundance may mask alterations in gene expression in individual cell types [211]. More recently, strategies to purify individual cardiac cell types have been developed that allow generation of cell type transcriptomes and which can provide insights into mechanisms underlying disease associated phenotypic repro-gramming [213,214].…”

Section: Systemic Small Molecule Therapy or Local Bz Targeted Therapymentioning

confidence: 99%

Ventricular Arrhythmias in Ischemic Cardiomyopathy—New Avenues for Mechanism-Guided Treatment

Amoni

Dries

Ingelaere

et al. 2021

Cells

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Ischemic heart disease is the most common cause of lethal ventricular arrhythmias and sudden cardiac death (SCD). In patients who are at high risk after myocardial infarction, implantable cardioverter defibrillators are the most effective treatment to reduce incidence of SCD and ablation therapy can be effective for ventricular arrhythmias with identifiable culprit lesions. Yet, these approaches are not always successful and come with a considerable cost, while pharmacological management is often poor and ineffective, and occasionally proarrhythmic. Advances in mechanistic insights of arrhythmias and technological innovation have led to improved interventional approaches that are being evaluated clinically, yet pharmacological advancement has remained behind. We review the mechanistic basis for current management and provide a perspective for gaining new insights that centre on the complex tissue architecture of the arrhythmogenic infarct and border zone with surviving cardiac myocytes as the source of triggers and central players in re-entry circuits. Identification of the arrhythmia critical sites and characterisation of the molecular signature unique to these sites can open avenues for targeted therapy and reduce off-target effects that have hampered systemic pharmacotherapy. Such advances are in line with precision medicine and a patient-tailored therapy.

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“…Moreover, the aforementioned differences in rodent and human ploidy limits the predictive power of experiments in mouse models. Studies of ploidy in primary human cardiomyocytes have begun to emerge (Hesse et al, 2021), and may be the best approach to elucidate its impact on inter-chromosomal genome architecture.…”

Section: Cardiac Inter-chromosomal Genome Organizationmentioning

confidence: 99%

RNA Biogenesis Instructs Functional Inter-Chromosomal Genome Architecture

Bertero

2021

Front. Genet.

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Three-dimensional (3D) genome organization has emerged as an important layer of gene regulation in development and disease. The functional properties of chromatin folding within individual chromosomes (i.e., intra-chromosomal or in cis) have been studied extensively. On the other hand, interactions across different chromosomes (i.e., inter-chromosomal or in trans) have received less attention, being often regarded as background noise or technical artifacts. This viewpoint has been challenged by emerging evidence of functional relationships between specific trans chromatin interactions and epigenetic control, transcription, and splicing. Therefore, it is an intriguing possibility that the key processes involved in the biogenesis of RNAs may both shape and be in turn influenced by inter-chromosomal genome architecture. Here I present the rationale behind this hypothesis, and discuss a potential experimental framework aimed at its formal testing. I present a specific example in the cardiac myocyte, a well-studied post-mitotic cell whose development and response to stress are associated with marked rearrangements of chromatin topology both in cis and in trans. I argue that RNA polymerase II clusters (i.e., transcription factories) and foci of the cardiac-specific splicing regulator RBM20 (i.e., splicing factories) exemplify the existence of trans-interacting chromatin domains (TIDs) with important roles in cellular homeostasis. Overall, I propose that inter-molecular 3D proximity between co-regulated nucleic acids may be a pervasive functional mechanism in biology.

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Proximity to injury, but neither number of nuclei nor ploidy define pathological adaptation and plasticity in cardiomyocytes

Cited by 13 publications

References 35 publications

Polyploid cardiomyocytes: implications for heart regeneration

Polyploid cardiomyocytes: implications for heart regeneration

Ventricular Arrhythmias in Ischemic Cardiomyopathy—New Avenues for Mechanism-Guided Treatment

RNA Biogenesis Instructs Functional Inter-Chromosomal Genome Architecture

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