555Cardiac regeneration from activated epicardium

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The mammalian heart has a very limited regenerative capacity. Cardiomyocytes, lost after ischemia, are replaced by fibroblasts. Although the human heart is able to form new cardiomyocytes throughout its lifespan, the efficiency of this phenomenon is not enough to substitute sufficient myocardial mass after an infarction. In contrast, zebrafish hearts regenerate through epicardial activation and initiation of myocardial proliferation. We have used the mWt1/IRES/GFP-Cre mouse line to trace the fate of epicardial derived cells during development and subsequently used this line to obtain insights into the activation and cellular contribution of the epicardium in response to ischemia.

Epicardial derived cells (EPDCs) start to populate the ventricular myocardium from E12 onward. Remarkably the EPDCs only populate the compact layer and it is only at the end of gestation that the EPDCs invade the trabecular myocardium. Within the developing myocardium the myocardium the EPDCs also contribute to a subset of the coronary endothelial cells and perivascular fibroblasts. In this mouse model we subsequently induced a myocardial infarction and analyzed the spatio-temporal changes in expression of embryonic epicardial, EMT, and stem cell markers and the contribution of the epicardial-lineage to the infarcted area. Immediately after the myocardial infarction the integrity of the epicardial layer overlaying the infarct is lost. The epicardium was found to regenerate within three days post infarction. In this regenerated epicardium, the embryonic gene program is transiently re-expressed as well as proliferation. Concomitant with this activation, EPDCs are formed until two weeks post-infarction. These EPDCs initially form a thick layer in between the newly fromed epicardium and ischemic myocardium. Subsequently, these mesenchymal cells replace the cardiomyocytes lost due to the ischemia and contribute to the fibroblast population, myofibroblasts and coronary endothelium in the infarct. From one month post infarction onward a small number of lineage postive cardiomyocytes is found within the infarcted zone.

We show that the contribution of epicardial derived cells to the froming ventricle and that an endogenous, epicardium-dependent regenerative response to injury is induced. Although this regenerative response leads to the formation of new cardiomyocytes, their number is insufficient. These molecular and cellular analyses provide basic knowledge essential for investigations on the regeneration of the mammalian heart aiming at epicardium-derived cells.

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