# Cell Therapy in the Treatment of Coronary Heart Disease
## 3 Cardiac Origin Cells for Cardiac Cell Therapy
### Epicardium-Derived Progenitor Cells  
The epicardium, consisting of epicardial mesothelial cells, collagen, and elastic fibers, is the outer layer of the heart wall in close proximity to the myocardium. The formation of a functional heart during embryogenesis is a result of interactions between the cardiogenic mesoderm, cardiac neural crest, and propeicardium [91]. In nearly all vertebrates, the propeicardium is a cluster of progenitor cells located at the venous pole of the embryonic heart [92]. During embryogenesis, epicardial progenitor cells (EPDCs) emerge in the epithelial-mesenchymal transition and contribute to the growth of cardiac fibroblasts, smooth muscle cells, and pericytes [93]. From the latter half of embryonic development, epicardial mesothelial cells progressively lose their capability to proliferate, convert into a layer of dormant epicardial cells, and persist in the postnatal period [94]. It has been widely believed that EPDCs are functionally inactive in the adult heart. However, recent studies suggest that they may contribute to the regeneration of cardiac tissue during age-related changes or after myocardial damage [95]. A coherent and firmly established comprehensive understanding of these factors is yet to be established. However, diverse animal models have demonstrated that the epicardium participates in bidirectional paracrine signaling, stimulating the proliferation of cardiomyocytes, attracting macrophages, and promoting the development and maturation of coronary vessels [96]. Current evidence suggests that the epicardium is composed of distinct subpopulations of cells with different abilities to upregulate embryonic gene expression (_Wt1_, _Raldh2_, _Tbx18_), promote proliferation, and induce epithelial-mesenchymal transition in response to cardiac injury, which has important clinical implications and potential therapeutic applications [97]. Once activated, the epicardium releases mitogenic signaling factors to cardiomyocytes, promoting cardiac regeneration [98; 99]. TGFb, PDGF, FGF, IGF, BMP, retinoic acid, Notch, NF-kB, Hippo/Yap, Sonic Hedgehog, Wnt/\(\beta\)-catenin signaling pathways, and extracellular matrix proteins are the major regulators of this process that have been identified to date [97]. It has been shown that epicardial mesothelial cells in the adult human heart are able to give rise to cardiac stromal cells that express the c-Kit receptor during the epithelial-mesenchymal transition [100]. Thus, EPDCs' regenerative potential is regulated by paracrine factor release and specific reactions to activated signaling pathways. However, direct participation in cardiomyocyte formation from EPDCs was not observed [93]. To initiate regenerative processes in the damaged adult heart, activation of the epicardium is required, with a focus on neovascularization and regeneration, while inhibiting the fibrocytic pathway and pro-inflammatory elements. The first pharmacological attempt to influence these processes involved the administration of thymosin \(\beta\)4, which plays a role in the vascularization of the neonatal heart [101]. In experiments that modeled MI in mice, results indicated that pre-treatment with thymosin \(\beta\)4 activated quiescent EPDCs, which subsequently raised the angiogenesis levels in the targeted tissues [101; 102]. However, activation of EPDCs was not observed when administering thymosin \(\beta\)4 during the early post-infarction period [103]. Other researchers have utilized profheticin-1 and VEGF-A for the same purposes [104; 105]. Additionally, a study has revealed that subepicardial implantation of collagen patches containing Fstl-1, a protein secreted by epicardial cells responsible for myocardial regeneration, partially improves cardiac contractile function in mice and pigs with induced MI [106]. Thus, the effects on the epicardium represent a novel approach to addressing the intricate problem of therapeutically regenerating CHD.