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    • In order to determine whether the neonatal

    2018-11-06

    In order to determine whether the neonatal mammalian heart harbors any significant regenerative capacity, we recently developed a surgical model of cardiac injury in 1-day-old neonatal mice (Fig. 1) (Porrello et al., 2011a). Following amputation of a portion of the ventricular apex comprising approximately 15% of the ventricle, neonatal mice mounted a regenerative response that restored the lost myocardial tissue over a period of 3weeks. Apical resection injury was associated with a series of cellular events highly reminiscent of cardiac regeneration in lower vertebrates, including formation of a blood clot, recruitment of inflammatory shk to the site of injury, epicardial cell activation, early extracellular matrix deposition, cardiomyocyte proliferation and restoration of normal cardiac function (Porrello et al., 2011a). The ability to efficiently regenerate heart muscle following amputation was lost by postnatal day 7, coinciding with the developmental window when rodent cardiomyocytes begin to lose their proliferative potential (Li et al., 1996; Soonpaa and Field, 1997). Genetic lineage tracing studies confirmed that the vast majority of regenerated cardiomyocytes in 1-day-old mice were derived from pre-existing cardiomyocytes through cell proliferation (Porrello et al., 2011a). However, a minor contribution of non-myocytes to neonatal cardiac regeneration could not be excluded due to limitations in the cardiomyocyte labeling efficiency that could be achieved using the tamoxifen-inducible Myh6-MerCreMer transgenic system (~70–80% in P1 mice) (Porrello et al., 2011a). More recent studies by our group and others suggest that 1-day-old neonatal mice are also capable of undergoing cardiac regeneration following myocardial infarction, which is the leading cause of heart failure in humans (Haubner et al., 2012; Porrello et al., 2013). Myocardial ischemia was induced by permanent ligation of the left anterior descending coronary artery (LAD) in 1-day-old mice (Fig. 1). LAD ligation was associated with a marked reduction in myocardial viability and a dramatic decline in cardiac function at day 3 following infarction (Porrello et al., 2013). However, within 3weeks, neonatal mice were able to launch a regenerative response that restored 95% of the infarcted myocardium and returned cardiac function to normal. Importantly, cardiac function was still unperturbed at 9months of age, suggesting that the neonatal regenerative response can sustain cardiac function for several months following injury (Porrello et al., 2013). Similar to cryocauterization in the zebrafish, neonatal infarction was associated with early collagen deposition, which later regressed and became marginalized to the periphery of the tissue. Little to no fibrosis was detectable at 3weeks following infarction, with the exception of a small region of tissue immediately adjacent to the ligature (Porrello et al., 2013). Histological and genetic lineage tracing studies confirmed that the majority of regenerated cardiomyocytes were derived from pre-existing cardiomyocytes through cell proliferation, similar to earlier studies in zebrafish, as well as following apical resection in neonatal mice (Haubner et al., 2012; Porrello et al., 2013). In addition, a robust angiogenic response was associated with heart regeneration in neonatal mice (Porrello et al., 2013). Corrosion casting of the coronary vasculature revealed large collateral vessels in the newly regenerated anterior wall of the left ventricle that had originated from the right side of the heart. Consistent with earlier studies using the apical resection model, 7- and 14-day-old mice failed to undergo cardiac regeneration following myocardial infarction, suggesting that cardiac regenerative capacity was lost within the first two weeks after birth in rodents (Porrello et al., 2013). These observations in 7-day-old mice were strikingly concordant with earlier studies by Robledo in the 1950s, which noted an incomplete cardiac regenerative response in 4–7 day-old rats following myocardial burn injury using a heated wire (Robledo, 1956). Collectively, these findings suggest that the neonatal heart has a robust capacity for cardiac regeneration following multiple forms of tissue damage, including myocardial infarction, but this regenerative potential is rapidly silenced after birth.