Cardiomyocytes Replicate and their Numbers Increase in Young Hearts

Naqvi, Nawazish; Singh, Ramesh; Iismaa, Siiri E.; Li, Ming; Calvert, John W.; Martin, David I. K.; Harvey, Richard P.; Graham, Robert M.; Husain, Ahsan

doi:10.1016/j.cell.2015.10.038

Cited by 16 publications

(15 citation statements)

References 10 publications

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“…Although some had also observed increases in murine cardiomyocytes during this postnatal developmental window (cf. ref 10 and also discussion in ref 7) and cardiomyocyte proliferation in humans has been shown to contribute to myocardial growth during the first 20 years of life11, others who sought to confirm our findings reported negative results6,12,13. These studies included sequential assessments of S phase and mitosis as well as cardiomyocyte number assessments using the emerging method of design-based stereology.…”

Section: Introductionmentioning

confidence: 47%

DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

Bogush

Lin

Naib

et al. 2020

Preprint

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A developmental surge in thyroid hormone (T3) after postnatal day-10 (P10), in mice, results in a burst of cardiomyocyte proliferation. This finding remains controversial, which could arise from perceived homogeneity of myocardial sampling for immunoblotting and immunohistochemical studies, or from differences in enzymatic digestion efficiency for cardiomyocyte isolation used to determine total ventricular cardiomyocyte numbers. Using a highly efficient (>97%) method for cardiomyocyte isolation, we show that exogenous T3 administered in vivo to post-neonatal (after postnatal P6) mice increased cardiomyocyte numbers. Using S- and M-phase markers, and lineage-tracing tools to assay for cell cycle activation and cytokinesis, respectively, we show that the T3-mediated increase in cardiomyocytes is confined to cells of the left ventricular (LV) apex; such spatial heterogeneity also being observed during normal development, which might confound substantiation of developmental increases in cardiomyocyte proliferation. In these apical cardiomyocytes, T3 stimulates proliferative ERK1/2 signaling, whereas those in the LV base are tonically inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. In P21 Dusp5–/– mice, cardiomyocyte endowment and LV mass are increased relative to age-matched wild-type controls, suggesting that DUSP5 regulates early heart growth. Identification of mechanisms regulating cardiomyocyte proliferation may allow development of cardiac regenerative therapies.

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Section: Introductionmentioning

confidence: 47%

DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

Bogush

Lin

Naib

et al. 2020

Preprint

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“…This conclusion is supported by recent observations that in the mouse there is a limited, thyroid hormone‐regulated burst in nuclear proliferation at PN14–15 (Naqvi et al . , ). Malnutrition during the suckling period, either because the dams are suckling a large litter (Fiorotto & Davis, ) or are fed a low‐protein diet (Ramos et al .…”

Section: Discussionmentioning

confidence: 99%

Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

Ferguson

Monroe

Heredia

et al. 2019

The Journal of Physiology

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Key points Impaired growth during fetal life can reprogramme heart development and increase the risk for long‐term cardiovascular dysfunction. It is uncertain if the developmental window during which the heart is vulnerable to reprogramming as a result of inadequate nutrition extends into the postnatal period. We found that adult female mice that had been undernourished only from birth to 3 weeks of age had disproportionately smaller hearts compared to males, with thinner ventricle walls and more mononucleated cardiomyocytes. In females, but not males, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited and maximal exercise capacity was compromised. These data suggest that the developmental window during which the heart is vulnerable to reprogramming by inadequacies in nutrient intake may extend into postnatal life and such individuals could be at increased risk for a cardiac event as a result of strenuous exercise. Abstract Adults who experienced undernutrition during critical windows of development are at increased risk for cardiovascular disease. The contribution of cardiac function to this increased disease risk is uncertain. We evaluated the effect of a short episode of postnatal undernutrition on cardiovascular function in mice at the whole animal, organ, and cellular levels. Pups born to control mouse dams were suckled from birth to postnatal day (PN) 21 on dams fed either a control (20% protein) or a low protein (8% protein) isocaloric diet. After PN21 offspring were fed the same control diet until adulthood. At PN70 V̇O2, max was measured by treadmill test. At PN80 cardiac function was evaluated by echocardiography and Doppler analysis at rest and following β‐adrenergic stimulation. Isolated cardiomyocyte nucleation and Ca2+ transients (with and without β‐adrenergic stimulation) were measured at PN90. Female mice that were undernourished and then refed (PUN), unlike male mice, had disproportionately smaller hearts and their exercise capacity, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited. A reduced left ventricular end diastolic volume, impaired early filling, and decreased stored energy at the beginning of diastole contributed to these impairments. Female PUN mice had more mononucleated cardiomyocytes; under resting conditions binucleated cells had a functional profile suggestive of increased basal adrenergic activation. Thus, a brief episode of early postnatal undernutrition in the mouse can produce persistent changes to cardiac structure and function that limit exercise/functional capacity and thereby increase the risk for the development of a wide variety of cardiovascular morbidities.

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“…Importantly, ki67 lineage tracing followed up to 1.5 years in the same experimental settings failed to identify CPCs or CSCs among the sources of any cycling population, in contrast to a limited yet existing fraction of cycling cardiomyocytes (0.16% of cycling myocardial cells) emerged from pre-existing cardiomyocytes (39). Although previous studies suggested that during preadolescence a native cardiomyocyte number expansion occurs (40, 41), this is under debate (42, 43), and it is believed that the dramatic increase in mammalian cardiac size during this period is due to cardiomyocyte hypertrophy rather than proliferation (44).…”

Section: Cardiac Subpopulations and The Contribution Of Innate Immunitymentioning

confidence: 99%

Three in a Box: Understanding Cardiomyocyte, Fibroblast, and Innate Immune Cell Interactions to Orchestrate Cardiac Repair Processes

Psarras

Beis

Nikouli

et al. 2019

Front. Cardiovasc. Med.

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Following an insult by both intrinsic and extrinsic pathways, complex cellular, and molecular interactions determine a successful recovery or inadequate repair of damaged tissue. The efficiency of this process is particularly important in the heart, an organ characterized by very limited regenerative and repair capacity in higher adult vertebrates. Cardiac insult is characteristically associated with fibrosis and heart failure, as a result of cardiomyocyte death, myocardial degeneration, and adverse remodeling. Recent evidence implies that resident non-cardiomyocytes, fibroblasts but also macrophages -pillars of the innate immunity- form part of the inflammatory response and decisively affect the repair process following a cardiac insult. Multiple studies in model organisms (mouse, zebrafish) of various developmental stages (adult and neonatal) combined with genetically engineered cell plasticity and differentiation intervention protocols -mainly targeting cardiac fibroblasts or progenitor cells-reveal particular roles of resident and recruited innate immune cells and their secretome in the coordination of cardiac repair. The interplay of innate immune cells with cardiac fibroblasts and cardiomyocytes is emerging as a crucial platform to help our understanding and, importantly, to allow the development of effective interventions sufficient to minimize cardiac damage and dysfunction after injury.

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Cardiomyocytes Replicate and their Numbers Increase in Young Hearts

Cited by 16 publications

References 10 publications

DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

Three in a Box: Understanding Cardiomyocyte, Fibroblast, and Innate Immune Cell Interactions to Orchestrate Cardiac Repair Processes

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