Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development.
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.
Department of Anatomy & Developmental Biology, Monash University, Wellington Road, Clayton VIC 3800, Melbourne, Australia.
Jörg-Detlef
JD
Drenckhahn
Quenten P
QP
Schwarz
Stephen
S
Gray
Adrienne
A
Laskowski
Helen
H
Kiriazis
Ziqiu
Z
Ming
Richard P
RP
Harvey
Xiao-Jun
XJ
Du
David R
DR
Thorburn
Timothy C
TC
Cox
D000818:Animals; D004622:Embryo, Mammalian; D005260:Female; D005318:Fetal Heart / Q000196:embryology*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006579:Heterozygote; D006706:Homeostasis; D008190:Lyases / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009030:Mosaicism / Q000196:embryology; D009206:Myocardium / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000502:physiology* / Q000648:ultrastructure; D038081:Organogenesis / Q000235:genetics*; D011247:Pregnancy; D019076:Transgenes; D049951:X Chromosome Inactivation; D001616:beta-Galactosidase / Q000235:genetics
D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase; D008190:Lyases