Journal Article

Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish

Dickson, Amy L, Poss, Kenneth D, Gemberling, Matthew, Karra, Ravi

2015

Overview

Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program. Heart attacks—which are a major cause of death in humans—occur when a blocked blood vessel stops blood from flowing to the heart. This causes many heart muscle cells to die, which can result in permanent damage that makes survivors more susceptible to heart failure in the future. A major goal of regenerative medicine is to develop therapies that can improve the recovery of heart muscle cells after a heart attack and restore normal heart activity to patients with heart failure. Unlike the human heart, the heart of an adult zebrafish is able to regenerate even after extensive damage. After an injury, the remaining heart muscle cells divide to replace the lost heart muscle, but it is not clear how this works. A protein called Neuregulin1 (or Nrg1 for short) can stimulate heart muscle cells to divide. Gemberling et al. investigated the role of this protein in the regeneration of the heart in adult zebrafish. The experiments show that when the heart is injured, the gene encoding the Nrg1 protein is switched on in cells of the outer layer of the heart wall. When Nrg1 is deliberately activated in uninjured adult zebrafish hearts, it causes the muscle cells to divide, leading to many new layers of heart muscle forming over the course of several weeks. Along with promoting cell division, Nrg1 also makes the heart muscle cells return to an immature state more like stem cells. Gemberling et al. found that Nrg1 also supports regeneration of the heart by changing the environment surrounding the muscle cells. For example, it stimulates the growth of new blood vessels and recruits non-muscle cells to the injury site. Gemberling et al.'s findings demonstrate that Nrg1 is sufficient to induce the growth of heart muscle growth in an adult animal, even in the absence of injury. To develop its therapeutic potential, future work will also need to identify how the gene that encodes Nrg1 is switched on by injury and identify the other molecules that interact with Nrg1.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / cardiac hyperplasia / Cardiomegaly - pathology / cardiomyocyte / Cardiomyocytes / Cell cycle / Cell Proliferation / Danio rerio / Developmental Biology and Stem Cells / Echocardiography / epicardium / ErbB-2 protein / Experiments / Heart / Heart - physiology / Heart diseases / Heart failure / heart regeneration / Heart Ventricles - pathology / Hyperplasia / Mitogens - metabolism / Myocardium / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Neuregulin-1 - metabolism / Neuregulin1 / Regeneration / Rodents / Signal Transduction / Stem cells / Swimming / Vascularization / Zebrafish / Zebrafish - physiology / Zebrafish Proteins - metabolism