Zhao, L., Borikova, A.L., Ben-Yair, R., Guner-Ataman, B., MacRae, C.A., Lee, R.T., Burns, C.G., and Burns, C.E. (2014) Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration. Proceedings of the National Academy of Sciences of the United States of America. 111(4):1403-1408.
The human heart’s failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the
worldwide morbidity and mortality associated with coronary artery disease. Remarkably, certain vertebrate species, including
the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes.
Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here,
we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular
apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium.
Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration
and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation,
and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial
tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial
regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease
in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte
proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration.
Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in