Mammalian Fetal Cardiac Regeneration After Myocardial Infarction Is Associated With Differential Gene Expression Compared With the Adult

Abstract

Background In adults, MI results in a brisk inflammatory response, myocardium loss and scar formation. We have recently reported the first mammalian large animal model of cardiac regeneration following MI in fetal sheep. We hypothesize that the fetus ability to regenerate functional myocardium following MI is due to differential gene expression regulating the response to MI in the fetus compared to the adult. Methods MI was created in adult (n=4) or early gestation fetal (n=4) sheep. Tissue harvested after 3 or 30 days, RNA extracted for microarray, followed by PCA and global gene expression analysis for the gene ontology (GO) terms: “response to wounding”, “inflammatory response”, “extracellular matrix”, “cell cycle”, “cell migration”, “cell proliferation” and “apoptosis”. Results PCA demonstrated that the global gene expression pattern in adult infarcts was distinctly different from uninfarcted region at 3 days and remained different 30 days post-MI. In contrast, gene expression in the fetal infarct was different from the uninfarcted region at 3 days, but by 30 days it returned to a baseline expression pattern similar to the uninfarcted region. 3 days post-MI there was an increase in the expression of genes related to all GO terms in fetal and adult infarcts, but this increase was much more pronounced in adults. By 30 days, the fetal gene expression returned to baseline, whereas in the adult remained significantly elevated. Conclusions These data demonstrate that the global gene expression pattern is dramatically different in the fetal regenerative response to MI compared to the adult response and may partly be responsible for the regeneration.

Label‐free imaging of healthy and infarcted fetal sheep hearts by two‐photon microscopy

“…The healing and repair process following MI differs in the fetus compared to the adult. Injured fetal hearts can recover from a MI event via proliferation of cardiomyocytes at the site of the infarction and surrounding border zone, and this involves low‐grade inflammation . While the fetal heart does not form a permanent collagenous scar, considerable extracellular matrix deposition occurs in the first week following MI in neonatal rodents .…”

Feasibility of detecting myocardial infarction in the sheep fetus using late gadolinium enhancement CMR imaging

“…Sheep are one of the most commonly used large animals for research into perinatal cardiac physiology because of the similarities with humans in terms of the timing of development relative to birth, fetal size and the number of foetuses [ 13 – 15 , 22 ]. Unlike the adult heart, the fetal heart responds to MI with a different gene expression profile, better recovery of cardiac function, diminished inflammatory response and no fibrosis [ 13 – 15 ]. Understanding the mechanism of fetal cardiac regeneration could help us develop ways to regenerate the myocardium in the injured adult heart.…”

“…However, after acute irreversible myocardial injury, contrast enters the intracellular space due to disruptions in cell membranes and becomes trapped for a period of time in reperfused cardiac tissue. The fetal myocardium has different cardiomyocyte characteristics, extracellular matrix components, and response to MI, compared with the adult heart [ 13 – 15 , 43 ]. For example, fetal cardiomyocytes are mononucleated and proliferative [ 44 , 45 ].…”

“…A fetal sheep model of MI has allowed researchers to investigate the mechanisms involved in fetal myocardial regeneration. The fetal response to MI is characterized by a distinct gene expression profile, elevated myocardial proliferation, diminished inflammation, lack of fibrosis, and better restoration of cellularity and cardiac function within 30 days when compared to adults [ 13 – 15 ]. Developing a method of detecting and monitoring the post-MI fetal heart could therefore help researchers study the mechanisms of cardiac regeneration in fetuses post-MI by promoting or inhibiting repair.…”

Hedgehog Signaling during Appendage Development and Regeneration

“…Recent studies support the notion that tissue injury and the regenerative response are associated with the activation of embryonic/fetal gene regulatory pathways during regeneration [ 33 , 34 ]. Regeneration is marked by distinct stages of architectural restoration including: wound healing, blastema formation, cellular proliferation and differentiation ( Figure 1 B) [ 11 , 19 , 35 , 36 , 37 , 38 ].…”