Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury

Bersell, Kevin; Arab, Shima; Haring, Bernhard; Kühn, Bernhard

doi:10.1016/j.cell.2009.04.060

Cited by 898 publications

(910 citation statements)

References 33 publications

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“…Analysis of isolated cardiomyocytes showed that M-phase cardiomyocytes were predominantly mononucleated (P < 0.001), which is in agreement with previous reports of cycling mononucleated cardiomyocytes in growing cats (19), rats (20), and mice (21).…”

Section: Resultssupporting

confidence: 91%

Cardiomyocyte proliferation contributes to heart growth in young humans

Mollova¹,

Bersell

Walsh³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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633

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The human heart is believed to grow by enlargement but not proliferation of cardiomyocytes (heart muscle cells) during postnatal development. However, recent studies have shown that cardiomyocyte proliferation is a mechanism of cardiac growth and regeneration in animals. Combined with evidence for cardiomyocyte turnover in adult humans, this suggests that cardiomyocyte proliferation may play an unrecognized role during the period of developmental heart growth between birth and adolescence. We tested this hypothesis by examining the cellular growth mechanisms of the left ventricle on a set of healthy hearts from humans aged 0-59 y (n = 36). The percentages of cardiomyocytes in mitosis and cytokinesis were highest in infants, decreasing to low levels by 20 y. Although cardiomyocyte mitosis was detectable throughout life, cardiomyocyte cytokinesis was not evident after 20 y. Between the first year and 20 y of life, the number of cardiomyocytes in the left ventricle increased 3.4-fold, which was consistent with our predictions based on measured cardiomyocyte cell cycle activity. Our findings show that cardiomyocyte proliferation contributes to developmental heart growth in young humans. This suggests that children and adolescents may be able to regenerate myocardium, that abnormal cardiomyocyte proliferation may be involved in myocardial diseases that affect this population, and that these diseases might be treatable through stimulation of cardiomyocyte proliferation.heart failure | pediatrics H eart failure, a leading public health problem worldwide (1), is linked to the loss of cardiomyocytes (2-4). The only currently available, definitive therapy-heart transplantation-is limited by donor availability. New approaches, such as cell transplantation, have shown encouraging results in clinical trials (5, 6). However, a third, complementary strategy has emerged, based on stimulating endogenous regenerative mechanisms. One approach for developing such regeneration strategies is to examine the cellular mechanisms of myocardial growth, since mechanisms of regeneration should be similar to the mechanisms of development.Although stem and progenitor cells are important for morphogenesis of the myocardium, developmental growth in a number of nonhuman species is largely driven by cardiomyocyte proliferation (7-9). In biological models that, unlike adult humans, regenerate myocardium, cardiomyocyte proliferation is important for regeneration as well as postnatal heart growth (10, 11). For example, in mice, developmental cardiomyocyte proliferation continues for up to day 7 after birth, which coincides with the loss of regenerative capacity (11,12). The close temporal relationship between cardiomyocyte proliferation and heart regeneration in animals raises the question of whether and to what age and extent cardiomyocyte proliferation plays a role in humans. The answer may help us understand the endogenous regenerative potential of the human heart and possibly indicate strategies for stimulating cardiomyocyte proliferation to reg...

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Section: Resultssupporting

confidence: 91%

Cardiomyocyte proliferation contributes to heart growth in young humans

Mollova¹,

Bersell

Walsh³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

633

578

View full text Add to dashboard Cite

show abstract

“…Instead, we observed that the effect of both cytokines combined was lower than either alone. Thus, as both proteins may utilize similar signaling pathways [15,17], it is possible that they compete, limiting their combined effect. Indeed, this important observation should be considered when designing new studies involving combination therapies.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to mediators of angiogenesis, the list of potential therapeutics for cardiac regeneration has continued to grow, and the use of factors involved in cardiac development, stem cell homing, cardiac differentiation/proliferation, or direct cardioprotection could lead to novel approaches for repairing damaged heart (reviewed in [4]). In this regard, in vitro studies have shown that adult cardiomyocytes do not proliferate under resting conditions, but may divide in response to extracellular mitogens, such as periostin [15], acidic fibroblast growth factor (FGF1) [16], and neuregulin-1 (NRG1) [17]. These findings have supported a new paradigm, which suggests that the heart might be capable of repair and regrowth in response to extracellular mitogens.…”

Section: Introductionmentioning

confidence: 98%

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

Formiga

Pelacho

Garbayo

et al. 2014

Journal of Controlled Release

100

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Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1-and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment was detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in preclinical and clinical studies.

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“…Studies have demonstrated that in addition to doxorubicin-induced heart failure, Neuregulin1 also improves cardiac function in ischemiareperfusion, viral infection, and pacing induced heart failure (Liu et al, 2006;Bersell et al, 2009;Hedhli et al, 2011). In addition, Neuregulin1 promotes cell cycle reentry of differentiated adult cardiomyocytes, improves angiogenesis in the heart (Bersell et al, 2009;Hedhli et al, 2011), and promotes embryonic stem cell differentiation into the cardiac lineage (Sun et al, 2011). Clinical trials are ongoing using Neureuglin1 for the treatment of heart failure in patients (Gao et al, 2010).…”

Section: Discussionmentioning

confidence: 99%