Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes

Bettencourt-Dias, Mónica; Mittnacht, Sybille; Brockes, Jeremy P.

doi:10.1242/jcs.00698

Cited by 127 publications

(104 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results uncovered a frequent re-entry into cell cycle of the p53 + lineage, suggesting more potent proliferative ability of this lineage and proliferative heterogeneity of cardiomyocytes in mice. This kind of proliferative heterogeneity of cardiomyocytes was discovered in newts and zebrafish (Bettencourt-Dias et al, 2003;Kikuchi et al, 2010). Our results implicate that this phenomenon is conserved in mammalian heart.…”

Section: Discussionsupporting

confidence: 74%

A p53-based genetic tracing system to follow postnatal cardiomyocyte expansion in heart regeneration

et al. 2017

View full text Add to dashboard Cite

In the field of heart regeneration, the proliferative potential of cardiomyocytes in postnatal mice is under intense investigation. However, solely relying on immunostaining of proliferation markers, the long-term proliferation dynamics and potential of the cardiomyocytes cannot be readily addressed. Previously, we found that a p53 promoter-driving reporter predominantly marked the proliferating lineages in mice. Here, we established a p53-based genetic tracing system to investigate postnatal cardiomyocyte proliferation and heart regeneration. By selectively tracing proliferative cardiomyocytes, a differential pattern of clonal expansion in p53 + cardiac myocytes was revealed in neonatal, adolescent and adult stages. In addition, the percentage of p53 + lineage cardiomyocytes increased continuously in the first month. Furthermore, these cells rapidly responded to heart injury and greatly contributed to the replenished myocardium. Therefore, this study reveals complex proliferating dynamics in postnatal cardiomyocytes and heart repair, and provides a novel genetic tracing strategy for studying postnatal cardiac turnover and regeneration.

show abstract

Section: Discussionsupporting

confidence: 74%

A p53-based genetic tracing system to follow postnatal cardiomyocyte expansion in heart regeneration

et al. 2017

View full text Add to dashboard Cite

show abstract

“…We used the percentage of cardiomyocytes in M-phase, which shows conservation of regulatory mechanisms and duration (∼1.5 h) between species, tissues, and ages (34)(35)(36). To calculate the number of cardiomyocytes generated from M-phase activity, determined by H3P analysis, we used the previously determined duration of 1.8 ± 0.3 h in adult ventricular cardiomyocytes (21,37). To correct our results for nonproductive mitotic events (binucleation, polyploidization), we multiplied by the age-specific percentage of mononucleated and diploid cardiomyocytes (from Fig.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte proliferation contributes to heart growth in young humans

Mollova¹,

Bersell

Walsh³

et al. 2013

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

645

578

View full text Add to dashboard Cite

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...

show abstract

“…Early studies indicated that adult amphibian and zebrafish cardiomyocytes undergo DNA synthesis and karyokinesis in response to injury at a frequency much greater than that seen in adult mammals (Bettencourt-Dias et al, 2003;Oberpriller and Oberpriller, 1974;Poss et al, 2002). The potential origins of proliferative cardiomyocytes could include undifferentiated progenitor cells, which were implicated in one report (Lepilina et al, 2006), or existing cardiomyocytes.…”

Section: Cardiomyocyte-intrinsic Programs For Natural Heart Regenerationmentioning

confidence: 99%

Building and re-building the heart by cardiomyocyte proliferation

2016

View full text Add to dashboard Cite

The adult human heart does not regenerate significant amounts of lost tissue after injury. Rather than making new, functional muscle, human hearts are prone to scarring and hypertrophy, which can often lead to fatal arrhythmias and heart failure. The most-cited basis of this ineffective cardiac regeneration in mammals is the low proliferative capacity of adult cardiomyocytes. However, mammalian cardiomyocytes can avidly proliferate during fetal and neonatal development, and both adult zebrafish and neonatal mice can regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation throughout life, deciphering why proliferative capacity normally dissipates in adult mammals, and deriving means to boost this capacity are primary goals in cardiovascular research. Here, we review our current understanding of how cardiomyocyte proliferation is regulated during heart development and regeneration.

show abstract

Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes

Abstract: ResultsNewt cardiomyocytes undergo DNA synthesis and mitosis in dissociated culture Adult newt cardiomyocytes were dissociated by proteolysis. Routinely, 40-60% of the cells obtained were cardiomyocytes,

Cited by 127 publications

References 47 publications

A p53-based genetic tracing system to follow postnatal cardiomyocyte expansion in heart regeneration

A p53-based genetic tracing system to follow postnatal cardiomyocyte expansion in heart regeneration

Cardiomyocyte proliferation contributes to heart growth in young humans

Building and re-building the heart by cardiomyocyte proliferation

Contact Info

Product

Resources

About