Unlocking cardiomyocyte renewal potential for myocardial regeneration therapy

Mehdipour, Melod; Park, Sang‐Soon; Huang, Guo N.

doi:10.1016/j.yjmcc.2023.02.002

Cited by 13 publications

(8 citation statements)

References 189 publications

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“…During our digital holographic imaging experiments, cardiomyocyte nuclei could be identified as round structures with approximately 10 μm diameters that have less overall vertical thickness. Polyploidization is thought to limit the proliferative potential of cardiomyocytes and is considered a major barrier to cardiac regeneration (Derks & Bergmann, 2020; Huang et al, 2023; Mehdipour et al, 2023). Therefore, we next determined if mononucleated and binucleated cardiomyocytes exhibited different proliferative responses to CHIR99021 stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…Cardiac primary cell culture represents a powerful in vitro approach to complement in vivo studies. Experiments using primary cardiomyocyte cultures from newborn rodents have revealed many intrinsic (e.g., transcription factors) and extrinsic (e.g., extracellular matrix proteins, secreted factors) regulators of cardiomyocyte proliferation and hypertrophy (Mehdipour et al, 2023). Therefore, primary cardiac cell culture is a relevant approach to investigate questions regarding heart development, physiology, and pathophysiology, especially at cellular and molecular levels.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Three-dimensional Label-free Digital Holographic Imaging of Cardiomyocyte Size, Ploidy, and Cell Division

Park,

Huang,

Ross

et al. 2023

Preprint

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Cardiac regeneration in newborn rodents depends on the ability of pre-existing cardiomyocytes to proliferate and divide. This capacity is lost within the first week of postnatal development when these cells rapidly switch from hyperplasia to hypertrophy, withdraw from the cell cycle, become binucleated, and increase in size. How these dynamic changes in size and ploidy impact cardiomyocyte proliferative potential is not well understood. In this study, we innovate the application of a commercially available digital holographic imaging microscope, the Holomonitor M4, to evaluate the proliferative responses of mononucleated diploid and binucleated tetraploid cardiomyocytes. This instrument coupled with the powerful Holomonitor App Suite software enables long-term label-free quantitative three-dimensional tracking of primary cardiomyocyte dynamics in real-time with single-cell resolution. Our digital holographic imaging results provide direct evidence that mononucleated cardiomyocytes retain significant proliferative potential as most can successfully divide with high frequency. In contrast, binucleated cardiomyocytes exhibit a blunted response to a proliferative stimulus with the majority not attempting to divide at all. Nevertheless, some binucleated cardiomyocytes were capable of complete division, suggesting that these cells still do retain limited proliferative capacity. By quantitatively tracking cardiomyocyte volume dynamics during these proliferative responses, we reveal that both mononucleated and binucleated cells reach a unique size threshold prior to attempted cell division. The absolute threshold is increased by binucleation, which may limit the ability of binucleated cardiomyocytes to divide. By defining the interrelationship between cardiomyocyte size, ploidy, and cell cycle control, we will better understand the cellular mechanisms that drive the loss of mammalian cardiac regenerative capacity after birth.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative Three-dimensional Label-free Digital Holographic Imaging of Cardiomyocyte Size, Ploidy, and Cell Division

Park,

Huang,

Ross

et al. 2023

Preprint

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“…Ordinarily, CD4 + T cells https://doi.org/10.1038/s41536-024-00357-z activate the innate immune system, cytotoxic T cells, B-lymphocytes, nonimmune cells, and include many subset cell populations with distinct roles in the natural immune response 70 . In non-regenerative P8 mice, ablation of CD4 + T cells was shown to increase regeneration after infarct, and neonatal mice reconstituted with adult T cells were shown to have a reduced regenerative response to alterations in the adaptive immune system [71][72][73] .…”

Section: Macrophages and Immune Cellsmentioning

confidence: 99%

Structural, angiogenic, and immune responses influencing myocardial regeneration: a glimpse into the crucible

Baccouche,

Elde,

Wang

et al. 2024

npj Regen Med

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Complete cardiac regeneration remains an elusive therapeutic goal. Although much attention has been focused on cardiomyocyte proliferation, especially in neonatal mammals, recent investigations have unearthed mechanisms by which non-cardiomyocytes, such as endothelial cells, fibroblasts, macrophages, and other immune cells, play critical roles in modulating the regenerative capacity of the injured heart. The degree to which each of these cell types influence cardiac regeneration, however, remains incompletely understood. This review highlights the roles of these non-cardiomyocytes and their respective contributions to cardiac regeneration, with emphasis on natural heart regeneration after cardiac injury during the neonatal period.

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“…In 2002, Kenneth Poss and his colleagues published a landmark paper showing that the adult zebrafish heart is fully capable of replenishing lost myocardial tissues without scars within 2 months after injury (Poss et al, 2002). Although previous researchers provided evidence of significant cardiomyocyte proliferation in adult newts, frogs, and lizards after myocardial injury (Mehdipour et al, 2023), this was the first compelling evidence of complete scarless heart regeneration in any adult vertebrate species. Being genetically tractable, zebrafish have since become a popular model to understand the cellular and molecular mechanisms underlying cardiac regeneration and repair.…”

Section: Introductionmentioning

confidence: 99%

Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond

Huang,

Payumo

2023

WIREs Mechanisms of Disease

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Interest in vertebrate cardiac regeneration has exploded over the past two decades since the discovery that adult zebrafish are capable of complete heart regeneration, contrasting the limited regenerative potential typically observed in adult mammalian hearts. Undercovering the mechanisms that both support and limit cardiac regeneration across the animal kingdom may provide unique insights in how we may unlock this capacity in adult humans. In this review, we discuss key discoveries in the heart regeneration field over the last 20 years. Initially, seminal findings revealed that pre‐existing cardiomyocytes are the major source of regenerated cardiac muscle, drawing interest into the intrinsic mechanisms regulating cardiomyocyte proliferation. Moreover, recent studies have identified the importance of intercellular interactions and physiological adaptations, which highlight the vast complexity of the cardiac regenerative process. Finally, we compare strategies that have been tested to increase the regenerative capacity of the adult mammalian heart.This article is categorized under: Cardiovascular Diseases > Stem Cells and Development

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Unlocking cardiomyocyte renewal potential for myocardial regeneration therapy

Cited by 13 publications

References 189 publications

Quantitative Three-dimensional Label-free Digital Holographic Imaging of Cardiomyocyte Size, Ploidy, and Cell Division

Quantitative Three-dimensional Label-free Digital Holographic Imaging of Cardiomyocyte Size, Ploidy, and Cell Division

Structural, angiogenic, and immune responses influencing myocardial regeneration: a glimpse into the crucible

Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond

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