br Introduction A key question

Introduction A key question in cardiovascular biology is to what degree the heart is able to regenerate after tissue damage from either cardiac stem cells or cardiomyocyte division. Cardiovascular disease including myocardial infarct is currently one of the leading causes of death worldwide, and the general view is that this is mainly caused by a genuine inability of the mammalian heart to regenerate upon damage (Vieira and Riley, 2011). Yet, this dogma was recently challenged by exciting data suggesting that the mouse heart retains regenerative ability up to 1 week after birth (Porrello et al., 2011), and without being reproduced by others, it has now been accepted as an established principle that neonatal mammalian hearts do enclose a true cardiac-regenerative potential following apex resection (AR) (Aguirre et al., 2013; Garbern and Lee, 2013). As a minimal requirement, complete cardiac regeneration should include the restoration of the functional continuity of cardiomyocytes, as well as blood supply in the necrotic area of the damaged heart with no sign of scar formation. Indeed, urodele neomycin sulfate and zebrafish have been shown to possess a high capacity to repair the heart following damage such as AR that meets these minimal criteria (Garbern et al., 2013). Accordingly, the zebrafish heart is regenerated in 60 days following AR, with full recovery of the myocardium (Poss et al., 2002). The mammal and zebrafish heart anatomy/physiology diverge substantially (Garbern et al., 2013). It was therefore a breakthrough in regenerative medicine of the mammalian heart when Porrello et al. in 2011 showed that the neonatal mouse heart (1 day old) holds an intrinsic capability to regenerate completely following resection of 10% of the heart apex (Porrello et al., 2011). As in the zebrafish heart (Jopling et al., 2010), the regenerative response in mice was primarily accomplished through reentry of cardiomyocytes into the cell cycle (Porrello et al., 2011). Interestingly, this ability was only transient and lost by postnatal day 7 (P7) (Porrello et al., 2011), a scenario the authors most recently suggested is caused by the homeobox transcription factor Meis1 inhibiting cardiomyocyte proliferation (Mahmoud et al., 2013). Remarkably, the repairing response seems to be faster in mice (21 days) (Porrello et al., 2011) than in teleost fish (60–180 days) (Lafontant et al., 2012; Poss et al., 2002). Furthermore, the regenerated neonatal mouse heart reportedly showed no signs of major scarring after 21 days (Porrello et al., 2011), which is in contrast to the mammalian adult heart that lacks substantial regenerative capacity (Garbern et al., 2013; Vieira and Riley, 2011). In addition, urodele amphibians and teleost fish show substantial scarring up until 60–180 days postinjury (Lafontant et al., 2012; Oberpriller and Oberpriller, 1974; Poss et al., 2002).
Results
Discussion Mortality after myocardial infarction is relatively high, and surviving patients are often severely compromised due to insufficient heart-pump function. At the cellular level, damage to the heart’s contractile constituents, the cardiomyocytes, is irreversible, and treatments merely serve to reduce symptoms, and only a minority of patients receives a heart transplant. Novel therapeutics to reestablish the cardiac tissue following infarcts are therefore needed, and factors improving heart regeneration will be of enormous value. The groundbreaking discovery of a mammalian regenerative heart model in mice (Porrello et al., 2011) has thus gained immense attention and hope for identifying factors that may improve cardiac regeneration. However, none of our results here suggests that the neonatal mammalian heart is able to accomplish complete regeneration following heart muscle resection as recently suggested by Porrello et al. (2011). Instead, we demonstrate that the resected heart apex remains lost and that the resection border is healed by a fibrotic scar composed of myofibroblasts, adipocytes, and sparse vessels. These nonmyogenic cells likely originate from the pericardium/epicardium (Smart et al., 2007; Zhou et al., 2008), the only structure in the apex that seemed completely regenerated. In contrast, we observed a lack of cardiac regeneration likely caused by a reduced number of proliferating cardiomyocytes within AR hearts as compared with noninjured hearts. Although the absolute number of proliferating cardiomyocytes would have been optimally determined by quantifying a proliferation marker in combination with a nuclear cardiomyocyte genetic label (Ang et al., 2010), our approach using EdU with cardiac myosin/collagen I seems valid for the relative measurements we performed, and importantly, Porrello et al. used a similar approach (Porrello et al., 2011). Our results are thus contradictory to those reported in the original study performed by the Sadek research group (Porrello et al., 2011).