Lamin B2 Levels Regulate Polyploidization of Cardiomyocyte Nuclei and Myocardial Regeneration

Han, Lu; Choudhury, Sangita; Mich-Basso, Jocelyn Danielle; Ammanamanchi, Niyatie; Ganapathy, Balakrishnan; Suresh, Sangita; Khaladkar, Mugdha; Singh, Jennifer M.; Maehr, René; Zuppo, Daniel A.; Kim, Junhyong; Eberwine, James; Wyman, Samuel K.; Wu, Yijen; Kühn, Bernhard

doi:10.1016/j.devcel.2020.01.030

Cited by 65 publications

(71 citation statements)

References 53 publications

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“…Our results show that STAT3 is not be activated in Mydgf-treated CMs, indicating that STAT3 signaling is not involved in Mydgf-indcued CM proliferation. We also found that Mydgf deficiency reduced karyokinesis, and thereby increased ploidy, which is coincided with reported data 17 .…”

Section: Discussionsupporting

confidence: 92%

“…Unlike adult, neonatal mammalian heart is able to regenerate after various types of injury 8 , but this regenerative process seems to be limited to the first postnatal week 9 , 10 , which coincides with CM exiting from the cell cycle 11 - 13 , CM cell-cycle withdrawal during mammalian postnatal development is tightly coupled with CM polyploidization, an increase in nuclear DNA content 14 . It has been demonstrated that troponin I3 kinase levels 15 or insulin-like growth factor 1 16 could change the percentage of polyploid CM nuclei, which altered heart regeneration 17 .…”

Section: Introductionmentioning

confidence: 99%

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Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration

Wang

Feng

et al. 2020

Theranostics

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Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, was found to protect against cardiac injury following myocardial infarction (MI) in adult mice. We speculated that Mydgf might improve heart function via myocardial regeneration, which is essential for discovering the target to reverse heart failure. Methods: Two genetic mouse lines were used: global Mydgf knockout ( Mydgf-KO ) and Mydgf-EGFP mice. Two models of cardiac injury, apical resection was performed in neonatal and MI was performed in adult mice. Quantitative reverse transcription-polymerase chain reaction, western blot and flow cytometry were performed to study the protein expression. Immunofluorescence was performed to detect the proliferation of cardiomyocytes. Heart regeneration and cardiac function were evaluated by Masson's staining and echocardiography, respectively. RNA sequencing was employed to identify the key involved in Mydgf-induced cardiomyocyte proliferation. Mydgf recombinant protein injection was performed as a therapy for cardiac repair post MI in adult mice. Results: Mydgf expression could be significantly induced in neonatal mouse hearts after cardiac injury. Unexpectedly, we found that Mydgf was predominantly expressed by endothelial cells rather than macrophages in injured neonatal hearts. Mydgf deficiency impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation. Mydgf recombinant protein promoted primary mouse cardiomyocyte proliferation. Employing RNA sequencing and functional verification, we demonstrated that c-Myc/FoxM1 pathway mediated Mydgf-induced cardiomyocyte expansion. Mydgf recombinant protein improved cardiac function in adult mice after MI injury with inducing cardiomyocyte proliferation. Conclusion: Mydgf promotes cardiomyocyte proliferation by activating c-Myc/FoxM1 pathway and improves heart regeneration both in neonatal and adult mice after cardiac injury, providing a potential target to reverse cardiac remodeling and heart failure.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration

Wang

Feng

et al. 2020

Theranostics

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“…Regardless of mechanisms, Kaplan-Meier plots for LMNB1 -scaling genes in primary lung tumors include LMNB2, BRCA1, MKI67 , and TOP2A ( Fig.S3a, S4a,b,c ), all of which show poor survival for high expression ( Fig.S4d,e ). Recent studies of proliferating, embryonic cardiomyocytes suggest LMNB2 facilitates attachment of microtubules to centromeres 42 . Such survival predictions are perhaps consistent with LMNB1 -scaling in tumor but not normal liver tissue (per Fig.2b ) and with LMNB1 being a marker of proliferation.…”

Section: Resultsmentioning

confidence: 99%

“…Page 7 of 30 attachment of microtubules to centromeres 42 . Such survival predictions are perhaps consistent with LMNB1-scaling in tumor but not normal liver tissue (per Fig.2b) and with LMNB1 being a marker of proliferation.…”

Section: Gene-gene Scalingmentioning

confidence: 99%

Scaling concepts in ’omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival

Vashisth

Discher²,

Cho³

et al. 2021

Preprint

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Spatiotemporal relationships between genes expressed in tissues likely reflect physicochemical principles that range from stoichiometric interactions to co-organized fractals with characteristic scaling. For key structural factors within the nucleus and extracellular matrix (ECM), gene-gene power laws are found to be characteristic across several tumor types in The Cancer Genome Atlas (TCGA) and across single-cell RNA-seq data. The nuclear filament LMNB1 scales with many tumor-elevated proliferation genes that predict poor survival in liver cancer, and cell line experiments show LMNB1 regulates cancer cell cycle. Also high in the liver, lung, and breast tumors studied here are the main fibrosis-associated collagens, COL1A1 and COL1A2, that scale stoichiometrically with each other and superstoichiometrically with a pan-cancer fibrosis gene set. However, high fibrosis predicts prolonged survival of patients undergoing therapy and does not correlate with LMNB1. Single-cell RNA-seq data also reveal scaling consistent with the pan-cancer power laws obtained from bulk tissue, allowing new power law relations to be predicted. Lastly, although noisy data frustrate weak scaling, concepts such as stoichiometric scaling highlight a simple, internal consistency check to qualify expression data.

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“…Nuclear lamina filament Lamin B2 (Lmnb2) expression decreases after birth coinciding with the closure of the neonatal regenerative window in mice. It enables metaphase progression and its suppression increased CM polyploidization and reduced cardiac regeneration in neonatal mice (Han et al 2020 ).…”

Section: New Players: Cellular Participators and Molecular Regulatorsmentioning

confidence: 99%

Vertebrate cardiac regeneration: evolutionary and developmental perspectives

Cutie

Huang

2021

Cell Regen

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Cardiac 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.

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Lamin B2 Levels Regulate Polyploidization of Cardiomyocyte Nuclei and Myocardial Regeneration

Cited by 65 publications

References 53 publications

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration

Scaling concepts in ’omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival

Vertebrate cardiac regeneration: evolutionary and developmental perspectives

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