Neonatal Heart Regeneration

Abstract

Background: The adult mammalian heart is incapable of meaningful functional recovery after injury, and thus promoting heart regeneration is one of the most important therapeutic targets in cardiovascular medicine. In contrast to the adult mammalian heart, the neonatal mammalian heart is capable of regeneration after various types of injury. Since the first report in 2011, a number of groups have reported their findings on neonatal heart regeneration. The current review provides a comprehensive analysis of heart regeneration studies in neonatal mammals conducted to date, outlines lessons learned and poses unanswered questions. Methods: We performed a PubMed search using the keywords “neonatal” and “heart” and “regeneration.” In addition, we assessed all publications that cited the first neonatal heart regeneration reports: Porrello et al, Science, Feb 2011 for apical resection injury; Porrello et al, PNAS, Dec 2012 for coronary ligation injury; and Mahmoud et al, Nature Methods, Jan 2014 for surgical methodology. Publications were examined for surgical models used, timing of surgery, and postinjury assessment including anatomical, histological and functional assessment, as well as conclusions drawn. Results: We found 30 publications that performed neonatal apical resection, 19 publications that performed neonatal myocardial infarction by coronary artery ligation, and 6 publications that performed cryoinjury using liquid nitrogen-cooled metal probes. Both apical resection and ischemic infarction injury in neonatal mice result in a robust regenerative response, mediated by cardiomyocyte proliferation. On the other hand, several reports have demonstrated that cryoinjury is associated with incomplete heart regeneration in neonatal mice. Not surprisingly, several studies suggest that injury size, as well as surgical and histological techniques can strongly influence the observed regenerative response and final conclusions. Studies have utilized these neonatal cardiac injury models to identify factors that either inhibit or stimulate heart regeneration. Conclusions: Overall, there is consensus that both apical resection and coronary ligation injuries during the first two days of life result in heart regeneration in neonatal mammals, whereas cryoinjury was not associated with a similar regenerative response. This regenerative response is mediated by proliferation of pre-existing cardiomyocytes, and is modifiable by injury size and surgical technique, as well as metabolic, immunologic, genetic and environmental factors.

Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model

“…Using this model, we demonstrate that neonatal rats at age P1 are capable of natural heart regeneration after MI, resulting in minimal LV scar formation, as well as preservation of normal cardiac size and LV function despite ischemic injury. These results build upon previous observations that suggest that natural heart regeneration may be a conserved phenotype among many newborn mammals, possibly including humans [37].…”

“…Although substantial insights regarding natural heart regeneration have been gleaned from the neonatal murine model, several notable limitations of this small animal model may impede widespread adoption and experimental reproducibility. Due to the very small size of the P1 mouse heart (approximately 1-2 mm diameter), the learning curve for developing expertise and consistency with microsurgery for the neonatal mouse MI model can be formidable [37]. Tearing of the fragile LV tissue and the risk of fatal bleeding given the extremely low blood volume of the P1 mouse (<100 µL) [38] are among the technical challenges related to the small size of the P1 mouse heart.…”

Macrophage Plasticity and Function in the Eye and Heart

“…Recent insights into the mechanisms driving macrophage function have highlighted the role of organismal aging and its contributions to shifting macrophages from a disease-protective state to a disease-promoting phenotype (Box 2). In mammalian heart, past the neonatal period, macrophages lose their regenerative capacity and instead promote inflammation and fibrosis following myocardial injury [42]. Moreover, aged macrophages acquire a foam cell phenotype and can promote atherosclerotic plaque formation and plaque angiogenesis [43].…”

Adaptation within embryonic and neonatal heart environment reveals alternative fates for adult c-kit+ cardiac interstitial cells

“…Furthermore, direct fluorescence visualization of FUCCI readouts allowed monitoring of cCIC cell cycle progression in host myocardium. From the outset when cCIC delivery occurs at the optimal P3 time point (Figure A), the reparative capacity of the postnatal heart that is present at P1‐P2 has largely been lost coinciding with cardiomyocyte exodus from cell cycle and increases in local ECM stiffness . Comparable phenotypic traits with cCIC previously found in the fetal context include expression of Vim (Figure J) but lack cardiac lineage markers (Figure B,C).…”