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    • Adding to the growing repertoire of available cardiac injury

    2018-10-24

    Adding to the growing repertoire of available cardiac injury models for neonatal mice, Jesty et al. recently reported on the cardiomyogenic potential of neonatal mice following cryoinjury (Jesty et al., 2012). In response to cryoinfarction at 1–3days-of-age, neonatal mice underwent a marked cardiomyogenic response and regenerated a large proportion of the infarcted tissue over a period of 94days. Consistent with observations in the apical resection and myocardial infarction models, neonatal cryoinjury was associated with robust induction of cardiomyocyte proliferation throughout the heart (Fig. 1). However, in addition to cardiomyocyte proliferation, a contribution of c-kit+ cardiac progenitor AG 013736 to cardiomyogenesis and angiogenesis in the neonate was also noted, suggesting that a pool of cardiac progenitor cells may be capable of supporting cardiac regeneration in neonatal mice (Jesty et al., 2012). Although significant scar regression was observed in this model, it should be noted that regeneration was not complete at 94days following cryoinjury. In contrast, a very recent paper by Strungs et al. has reported complete regeneration of the neonatal heart following cryoinjury at P1 and this regenerative potential is lost by P7, similar to previous findings in apical resection and myocardial infarction models (Strungs et al., 2013). However, given that neither Jesty et al. nor Strungs et al. reported the size or reproducibility of neonatal cryoinfarcts, it is unclear whether the lack of complete regeneration in the Jesty et al. study is due to a larger infarct size or the degree of transmurality of the infarcts. Given that cryoablation of only 25% of the zebrafish heart is also associated with a much more protracted regenerative response (Gonzalez-Rosa et al., 2011), it will be important to assess the regenerative capacity of the neonatal mouse heart following small, large, superficial and transmural infarcts in the future in order to determine the physiological limits of neonatal heart regeneration. Although studies in rodents offer a powerful experimental approach to the developmental regulation of cardiac regeneration, it is well known that both the timing of cardiac maturation and the cardiovascular physiology of the rodent heart are different to large animals, such as humans (Botting et al., 2012). Therefore, systematic studies of heart regeneration at different developmental stages in large animal models are important. While the literature in this field is sparse, it has been reported that fetal sheep can undergo regenerative healing following myocardial infarction during early gestation (Allukian et al., 2013; Herdrich et al., 2010). Further studies are required to determine the precise timing and cellular mechanisms underlying regenerative arrest in AG 013736 large animal models, including whether this capacity extends into the immediate postnatal period.
    Cardiomyocyte proliferation contributes to cardiomyocyte replenishment during aging and following injury An underlying feature of cardiac regeneration in lower vertebrates and neonatal mice is the robust cardiomyocyte proliferative response (Oberpriller and Oberpriller, 1971; Poss et al., 2002; Porrello et al., 2011a; Porrello et al., 2013), which is absent in non-regenerative adult mammals. In contrast to zebrafish and newt cardiomyocytes, which remain predominantly mononucleated and retain proliferative potential throughout life, most mammalian cardiomyocytes permanently withdraw from the cell cycle before adulthood (Kikuchi and Poss, 2012). In rodents, cardiomyocytes undergo a final round of DNA synthesis and karyokinesis in the absence of cytokinesis, which results in the binucleation of the vast majority (90–95%) of cardiomyocytes by postnatal day 14 (Li et al., 1996; Soonpaa et al., 1996; Walsh et al., 2010). In contrast, binucleation in large mammals, such as sheep, is typically completed before birth (Jonker et al., 2007). Interestingly, the proportion of binucleated cardiomyocytes is much lower in humans than other mammals (~30–40%) (Mollova et al., 2013). Although the proportion of binucleated cardiomyocytes does not change after birth in humans, there is a significant increase in the number of polyploid cardiomyocytes from birth (~5%) to 40years of age (~60%) (Mollova et al., 2013). Indeed, a recent study by Mollova et al. indicates that cardiomyocytes continue to proliferate, albeit at a low rate, during the first 20years of human life (Mollova et al., 2013), suggesting that the “proliferative window” for human cardiomyocytes might extend well into childhood and adolescence.