Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression

Leone, Marina; Musa, Gentian; Engel, Felix B.

doi:10.1093/cvr/cvy056

Cited by 53 publications

(43 citation statements)

References 67 publications

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“…An interpretation of these findings is that centrosome disassembly might lead to cytoskeletal reorganization to better handle postnatal increased hemodynamic load, thanks to a more effective organization of the MTOC in correspondence to the nuclear envelope, as it also occurs in skeletal muscle . Failure to complete cytokinesis might also then ensue due to mislocalization of proteins required to form an effective actomyosin ring for cleavage furrow formation . Further studies will certainly reveal whether these are the cause or effects of mammalian CM withdrawal from the cell cycle, and to what extent these effects might be reversible.…”

Section: Dynamics Of the Centrosome During Cardiomyocyte Mitosis And mentioning

confidence: 99%

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

2019

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Adult mammals are unable to regenerate their hearts after cardiac injury, largely due to the incapacity of cardiomyocytes (CMs) to undergo cell division. However, mammalian embryonic and fetal CMs, similar to CMs from fish and amphibians during their entire life, exhibit robust replicative activity, which stops abruptly after birth and never significantly resumes. Converging evidence indicates that formation of the highly ordered and stable cytoarchitecture of mammalian mature CMs is coupled with loss of their proliferative potential. Here, we review the available information on the role of the cardiac cytoskeleton and sarcomere in the regulation of CM proliferation. The actin cytoskeleton, the intercalated disc, the microtubular network and the dystrophin-glycoprotein complex each sense mechanical cues from the surrounding environment. Furthermore, they participate in the regulation of CM proliferation by impinging on the yes-associated protein/transcriptional co-activator with PDZ-binding motif, b-catenin and myocardin-related transcription factor transcriptional co-activators. Mastering the molecular mechanisms regulating CM proliferation would permit the development of innovative strategies to stimulate cardiac regeneration in adult individuals, a hitherto unachieved yet fundamental therapeutic goal.

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Section: Dynamics Of the Centrosome During Cardiomyocyte Mitosis And mentioning

confidence: 99%

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

2019

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“…Cardiomyocytes establish a nuclear envelope MTOC shortly after birth and at the same time begin to enter a postmitotic state [243]. Yet, cardiomyocytes progress through one last cell cycle, which results in cytokinesis failure associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression [244]. The cytokinesis failure leads to polyploidy and polynucleated cardiomyocytes [218].…”

Section: Cell Cycle Exit and Regenerationmentioning

confidence: 99%

“…The cytokinesis failure leads to polyploidy and polynucleated cardiomyocytes [218]. It has been hypothesized that the last cardiomyocyte cell cycle occurs after the formation of the nuclear envelope MTOC [244]. Still, the putative causal relationship between cell cycle exit and nuclear envelope MTOC formation is unclear.…”

Section: Cell Cycle Exit and Regenerationmentioning

confidence: 99%

Microtubule Organization in Striated Muscle Cells

Becker

Leone

Engel

2020

Cells

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Distinctly organized microtubule networks contribute to the function of differentiated cell types such as neurons, epithelial cells, skeletal myotubes, and cardiomyocytes. In striated (i.e., skeletal and cardiac) muscle cells, the nuclear envelope acts as the dominant microtubule-organizing center (MTOC) and the function of the centrosome—the canonical MTOC of mammalian cells—is attenuated, a common feature of differentiated cell types. We summarize the mechanisms known to underlie MTOC formation at the nuclear envelope, discuss the significance of the nuclear envelope MTOC for muscle function and cell cycle progression, and outline potential mechanisms of centrosome attenuation.

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“…[54][55][56][57] The contractile actomyosin ring is formed during CM binucleation, which constricts the central spindle resulting in midbody formation. [57][58][59] While SPG20 plays a role in midbody abscission, 28 we tested whether our dual-MB strategy was capable of distinguishing cell divisions from binucleated events. P3 rat-CMs were treated with serum and an increase in the percentage of binucleated CMs was observed ( Fig.…”

Section: Distinguishing CM Division From Polyploidy and Binucleationmentioning

confidence: 99%

Isolation of cardiomyocytes undergoing mitosis with complete cytokinesis

Milliron

Weiland

Kort

et al. 2019

Preprint

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Rationale-Adult human cardiomyocytes (CMs) do not complete cytokinesis despite passing through the S-phase of the cell cycle. As a result polyploidization and multinucleation occur. In order to get a deeper understanding of the mechanisms surrounding division of CMs there is a crucial need for a technique to isolate CMs that complete cell division/cytokinesis.Objective-Markers of cell cycle progression based on DNA content cannot distinguish between mitotic CMs that fail to complete cytokinesis from those cells that undergo true cell division. With the use of molecular beacons (MB) targeting specific mRNAs we aimed to identify truly proliferative CMs derived from hiPSCs.Methods and Results-Fluorescence activated cell-sorting combined with molecular beacons was performed to sort CM populations enriched for mitotic cells. Expressions of cell-cycle specific genes were confirmed by means of RT-qPCR, single-cell RNA sequencing (scRNA-seq). We further characterized the sorted groups by proliferation assays and time-lapse microscopy which confirmed the proliferative advantage of MB-positive cell populations relative to MB-negative and G2/M populations. Gene expression analysis revealed that the MB-positive CM subpopulation exhibited patterns consistent with the biological processes of nuclear division, chromosome segregation, and transition from M to G1 phase. The use of dual-MBs targeting CDC20 and SPG20 mRNAs (CDC20 + SPG20 + ) enabled the enrichment of cytokinetic events. Interestingly, cells that did not complete cytokinesis and remained binucleated were found to be CDC20 -SPG20 + while polyploid CMs that replicated DNA but failed to complete karyokinesis were found to be CDC20 -SPG20 -.Conclusions-This study demonstrates a novel alternative to existing DNA content-based approaches for sorting CMs with true mitotic potential that can be used to study in detail the unique dynamics of CM nuclei during mitosis. Together with high-throughput scRNA-seq, our technique for sorting live CMs undergoing cytokinesis would provide a basis for future studies to uncover mechanisms underlying the development and regeneration of heart tissue.

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Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression

Cited by 53 publications

References 67 publications

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

Microtubule Organization in Striated Muscle Cells

Isolation of cardiomyocytes undergoing mitosis with complete cytokinesis

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