University of Southern California

Sucov Lab

USC Stem Cell

Embryonic cardiomyocyte proliferation and neonatal heart regeneration

Model of regulation of epicardial Igf2 expression and ventricular wall morphogenesis. After formation of the epicardium and prior to establishment of placental circulation, embryonic tissue is hypoxic, and the liver is a prominent source of EPO (green diamonds) that diffuses via coelomic fluid from the peritoneal cavity into the pericardial cavity through the pericardioperitoneal canals (open gaps in the diaphragm). EPO activates EPOR on the surface of the epicardium to induce expression of IGF2, which diffuses across the subepicardial space to activate myocardial IGF receptors and induce proliferation. After  the onset of placental function, embryonic tissue becomes normoxic and Epo expression in the liver declines, and at the same time the diaphragm closes. Placental glucose and oxygen from the heart lumen then maintain Igf2 expression in the epicardium. From Shen et al., 2015.

Model of regulation of epicardial Igf2 expression and ventricular wall morphogenesis. After formation of the epicardium and prior to establishment of placental circulation, embryonic tissue is hypoxic, and the liver is a prominent source of EPO (green diamonds) that diffuses via coelomic fluid from the peritoneal cavity into the pericardial cavity through the pericardioperitoneal canals (open gaps in the diaphragm). EPO activates EPOR on the surface of the epicardium to induce expression of IGF2, which diffuses across the subepicardial space to activate myocardial IGF receptors and induce proliferation. After the onset of placental function, embryonic tissue becomes normoxic and Epo expression in the liver declines, and at the same time the diaphragm closes. Placental glucose and oxygen from the heart lumen then maintain Igf2 expression in the epicardium. From Shen et al., 2015.

The epicardium is the outer noncontractile mesothelium of the heart. It initially forms by migration from a nearby origin, and once formed induces cardiomyocyte proliferation such that the ventricular wall increasingly thickens during the remainder of gestation. This is mechanically necessary for increasing heart functional output as the embryo itself grows.

We identified IGF2 as the major mitogenic signal secreted by the epicardium responsible for midgestation cardiomyocyte proliferation (Li et al., 2011). In our recent work (Shen et al., 2015), we found that epicardial Igf2 has two phases of regulation (see the figure). The first occurs prior to the onset of placental circulation and is mediated by secretion of erythropoietin (Epo) from the liver. After the onset of placental circulation, epicardial Igf2 is supported by the transfer of oxygen and glucose from the placenta. We used a number of genetic and cell-based experimental approaches to confirm these models.

Cardiomyocyte proliferation ceases around the time of birth. Nonetheless, the late embryonic and early neonatal heart retain the ability to reactivate cardiomyocyte proliferation after injury and thereby efficiently regenerate. This ability is mostly lost in the postnatal period (in mouse, by postnatal day 7), when most cardiomyocytes become permanently postmitotic. As an extension of our model that the principles of embryonic cardiomyocyte proliferation are relevant to understanding the process of postnatal heart regeneration, we found that IGF2 signaling is indispensable for neonatal heart regeneration (unpublished observations).

Current efforts are devoted to identifying the cellular source of the ligand in the neonatal heart, defining the specific receptor and its downstream signaling, and of course also studying IGF2 in the adult heart and its relevance to adult heart regeneration.