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

Dev Cell. 2008 Oct;15(4):521-33. doi: 10.1016/j.devcel.2008.09.005.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryo, Mammalian
  • Female
  • Fetal Heart / embryology*
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Heart / embryology*
  • Heterozygote
  • Homeostasis*
  • Lyases / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Models, Cardiovascular
  • Mosaicism / embryology
  • Myocardium / cytology
  • Myocardium / pathology
  • Myocardium / ultrastructure
  • Myocytes, Cardiac / physiology*
  • Myocytes, Cardiac / ultrastructure
  • Organogenesis / genetics*
  • Pregnancy
  • Transgenes
  • X Chromosome Inactivation
  • beta-Galactosidase / genetics

Substances

  • Green Fluorescent Proteins
  • beta-Galactosidase
  • Lyases