Compensatory Growth of Healthy Cardiac Cells in the Presence of Diseased Cells Restores Tissue Homeostasis during Heart Development

Abstract

Energy generation by mitochondrial respiration is an absolute requirement for cardiac function. Here, we used a heart-specific conditional knockout approach to inactivate the X-linked gene encoding Holocytochrome c synthase (Hccs), an enzyme responsible for activation of respiratory cytochromes c and c1. Heterozygous knockout female mice were thus mosaic for Hccs function due to random X chromosome inactivation. In contrast to midgestational lethality of Hccs knockout males, heterozygous females appeared normal after birth. Analyses of heterozygous embryos revealed the expected 50:50 ratio of Hccs deficient to normal cardiac cells at midgestation; however, diseased tissue contributed progressively less over time and by birth represented only 10% of cardiac tissue volume. This change is accounted for by increased proliferation of remaining healthy cardiac cells resulting in a fully functional heart. These data reveal an impressive regenerative capacity of the fetal heart that can compensate for an effective loss of 50% of cardiac tissue.

Concise Review: Heart Regeneration and the Role of Cardiac Stem Cells

“…With the exception of some tissues such as the liver, skin, and intestine, mammals have largely lost their regenerative potential following embryonic and the early postnatal period [20]. After an AMI, massive loss of cardiac myocytes is replaced by fibrosis and subsequent scar formation [23].…”

The Janus face of OSM-mediated cardiomyocyte dedifferentiation during cardiac repair and disease

“…12 Nevertheless, it came as a surprise that this property is maintained in newborn mice, although the mouse heart loses its regenerative potential within the first week of postnatal life. 13 Interestingly, neonatal hearts in various mammalian species also have a greater tolerance to hypoxia than adult animals.…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…1). Although fetal and neonatal hearts show a strong capacity for regeneration (Drenckhahn et al, 2008;Porrello et al, 2011), pathologies of the adult heart, including myocardial infarction and dilated cardiomyopathy, which are accompanied by severe loss of cardiomyocytes and functional output, are repaired through a process related to wound healing, leading to fibrosis. Here, tissue damage resulting from ischemia and inflammation overwhelms any endogenous regenerative response, with the outcome being scar formation, loss of tissue integrity and reduced cardiac contractile function.…”