Cardiac Regeneration from Activated Epicardium

Abstract

In contrast to lower vertebrates, 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. With this study we obtain insights into the activation and cellular contribution of the mammalian epicardium in response to ischemia. In a mouse myocardial infarction model we analyzed the spatio-temporal changes in expression of embryonic epicardial, EMT, and stem cell markers and the contribution of cells of the Wt1-lineage to the infarcted area. Though the integrity of the epicardial layer overlaying the infarct is lost immediately after the induction of the ischemia, it was found to be regenerated at three days post infarction. In this regenerated epicardium, the embryonic gene program is transiently re-expressed as well as proliferation. Concomitant with this activation, Wt1-lineage positive subepicardial mesenchyme is formed until two weeks post-infarction. These mesenchymal cells replace the cardiomyocytes lost due to the ischemia and contribute to the fibroblast population, myofibroblasts and coronary endothelium in the infarct, and later also to the cardiomyocyte population. We show that in mice, as in lower vertebrates, 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 in mice but sufficient in lower vertebrates to replace lost cardiomyocytes. These molecular and cellular analyses provide basic knowledge essential for investigations on the regeneration of the mammalian heart aiming at epicardium-derived cells.

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

“…Recent work has highlighted the emerging role that the epicardium plays in the developing heart as well as in the adult heart after myocardial injury (10,17,19,48). Studies have shown that the epicardium becomes relatively quiescent after development but that there is robust reactivation of multiple fetal gene programs in the setting of myocardial injury (6,8,49). One factor implicated in this reactivation is thymosin β4 (Tβ4).…”

“…Recently, a series of studies have demonstrated that the epicardium is activated following myocardial injury (6)(7)(8)(9)(10). The epicardium, the cellular layer adjacent to and surrounding the myocardium, was once considered a passive lining of the heart that provided a mechanical support to allow for optimal ventricular function (11,12).…”

“…During embryonic development, the epicardium can give rise to fibroblasts, smooth muscle cells, and endothelial cells within the heart (13,14). Furthermore, a regenerative role for the epicardium after myocardial injury has been suggested over the past decade, wherein epicardial activation and reexpression of fetal gene programs following MI allows for repair of injured myocardium through intermediary epicardium-derived cells (EPDCs) (6,10,(15)(16)(17)(18)(19), although this hypothesis is controversial (20). The activated epicardium after injury has also been implicated as a source of cytokines capable of modulating revascularization and repair of the damaged heart (21).…”

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

“…The epicardium has been reported to play an active role during normal cardiomyogenesis 25, while it becomes quiescent after birth 26. Although the mammalian epicardium is activated after MI, the number of the activated cells is insufficient for myocardium repair 27, 28. MSCs secrete anti‐inflammatory, immunosuppressive, anti‐apoptotic and proangiogenic factors 29, 30.…”

Analysis of the Role of Crim1 in Heart Development

“…The epicardium gives rise to crucial components of the developing heart, and while the differentiation of EPDCs into cardiomyocytes and coronary endothelial cells remains a controversial topic, reactivated epicardial cells after myocardial damage have been shown to give rise to fibroblast and smooth muscle cells [28][29][30][31][32] . The epicardium also has a critical role in providing instructive cues and trophic factors for the developing myocardium.…”