The epicardium as a source of multipotent adult cardiac progenitor cells: Their origin, role and fate

Abstract

Since the regenerative capacity of the adult mammalian heart is limited, cardiac injury leads to the formation of scar tissue and thereby increases the risk of developing compensatory heart failure. Stem cell therapy is a promising therapeutic approach but is facing problems with engraftment and clinical feasibility. Targeting an endogenous stem cell population could circumvent these limitations. The epicardium, a membranous layer covering the outside of the myocardium, is an accessible cell population which plays a key role in the developing heart. Epicardial cells undergo epithelial to mesenchymal transition (EMT), thus providing epicardial derived cells (EPDCs) that migrate into the myocardium and cooperate in myocardial vascularisation and compaction. In the adult heart, injury activates the epicardium, and an embryonic-like response is observed which includes EMT and differentiation of the EPDCs into cardiac cell types. Furthermore, paracrine communication between the epicardium and myocardium improves the regenerative response. The significant role of the epicardium has been shown in both the developing and the regenerating heart. Interestingly, the epicardial contribution to cardiac repair can be improved in several ways. In this review, an overview of the epicardial origin and fate will be given and potential therapeutic approaches will be discussed.

Developmental co-emergence of cardiac and gut tissues modeled by human iPSC-derived organoids

“…At early stages of in vitro culture, multilineage organoids resemble human fetal heart formation (~5 weeks of gestation), evidenced by the formation of a surface layer of epicardial cells and a core of cardiomyocytes that exhibit significant growth over long-term culture. The epicardium is an important source of IGF2, a potent cardiac mitogen involved in cardiac wall thickening (35,36), as well as cardiac fibroblasts and SMCs that invade the heart following an epithelial-to-mesenchymal transition (37). Similarly, in our organoid model, we observed cardiac expansion and WT1-positive cells outside the epicardial layer, as well as the later emergence of SMCs and endothelial cells (which occur at ~10 weeks of gestation in human fetal heart).…”

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

“…Several myofibroblast-related genes were elevated only at MI day 7 (Online Resource 4a), including Cdh2 (N-cadherin) [48, 58], Cdh11 (cadherin-11) [53], Itga11 (integrin alpha-11) [1, 57], Timp1 and Timp3 [56], and Tmsb4x (thymosin beta-4) [4]. We also found that Wt1 and Twist1 , markers of epicardial cell origin [52], were increased at day 7 (Online Resource 4c). Thbs1 was the highest ranked feature for differentially expressed genes by one-way ANOVA, being 3.2-fold increased at MI day 7 over day 0.…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…In the last few years, there have been high expectations that endogenous stromal cardiac mesenchymal cells, originally defined as cardiac progenitor cells (CPCs), were endowed with cardiomyogenic and cardiovascular commitment potential. Indeed, CPCs have been long considered as an appealing source for cardiac regeneration via their in situ reactivation, expansion and differentiation or, alternatively, by means of trans-differentiation of either autologous or allogeneic ones transplanted into the injured myocardium [48][49][50][51][52][53][54][55] Multiple independent investigators have reported several heterogeneous CPC populations according to specific isolation protocols and marker expression patterns [54][55][56][57][58][59][60]. Notably, CPCs and, in particular, epicardium-derived progenitor cells, namely EPDCs, have been suggested to play a pivotal role in modulating the underlying myocardium and directly supporting to coronary vascular smooth muscle cells, cardiac fibroblasts and possibly a small proportion of ventricular cardiomyocytes.…”