# The Telocytes in the Subepicardial Niche
## 4 Discussion
### Processes of Epicardial Transdifferentiation  
The transition of a cell from an epithelial to a mesenchymal phenotype, or EMT, has been shown to play critical roles in several physiological and pathological contexts, from embryogenesis to fibrosis and cancer progression [73]. The postnatal mammalian epicardium is a dormant single-cell layer [74]. After an injury, the adult epicardium is activated, which involves the induction of a developmental gene program, EMT and migration [75]. Several genes are involved in epicardial activation, including WT1 (Wilms' tumour 1), TBX18 and RALDH2 [74]. Human EPDCs closely resemble submesothelial fibroblasts and express cardiac marker genes, such as GATA4 and cardiac troponin T [76]. EPDCs display intense \(\beta\)-catenin staining, which supports their epithelial nature [76]. The reactivation of the epicardium occurs in ischaemia, with the re-expression of developmental genes and renewed EMT [77]. We have brought forward evidence of CK7 expression in EMCs as well as in isolated subepicardial stromal cells that could be viewed as EPDCs. To our knowledge, the CK7 marker has not been tested previously on human cardiac samples. CK7 should therefore be included in the list of known markers of EPDCs, such as \(\beta\)-catenin, CD44, CD46, CD90, CD105, HLA-ABC [76] and WT1 [78]. The expression of CD117/c-kit was also associated with EPDCs [46]. We also found c-kit expressed in mesothelial cells, which could indicate that the stem/progenitor phenotype of future EPDCs could be acquired prior to the stromal migration of the epithelial cells. During human cardiogenesis, ventricular and atrial epicardia exhibit different pan-cytokeratin expression patterns and cell arrangements; atrial epicardial cells are distributed in a stochastic fashion on the surface with a diffuse cytokeratin expression throughout the cytoplasm, whereas ventricular epicardial cells exhibit a spindle-cell morphology and preferential alignment, being orientated side-by-side with strong cytokeratin staining outlining the cell membrane and cytoskeletal filaments [79]. Polyclonal anti-keratin antibodies were used to stain the mesothelial and mesenchymal cells of the propiecardium, as well as epicardium, in quail embryos [80; 81], and not in human samples. Adult EPDCs can form tube-like structures [75]. Tangentially cut tube-like structures, if tangentially cut, could appear on slides or grids as TC-like cells [82]. We found such D2-40-expressing tubes immediately beneath the podoplanin-expressing epicardial mesothelium, which strongly suggests that subepicardial lymphatics could acquire an epicardial-based support for their maintenance. In a static two-dimensional TEM study of epicardial ICLCs, [PERSON] and [PERSON] observed that mesenchymal cells, 'guided by ICLCs, were found migrating from [the] sub-epicardial area in the mesothelial layer'; that is, they were'migrating under the basal lamina of the epicardial mesothelial cell' [29]. The authors also speculated that 'epithelial-mesenchymal transition is not a common process involved in cardiac regeneration in vivo' [29]. That concept inspired us to document the processes of mesenchymal-epithelial transition (MET) mentioned by this TEM study. TGF\(\beta\)-induced EMT could be reversed through inhibition of the Smad2 signaling pathway [83]. Serum-free culture media, as well as TGF\(\beta\) receptor inhibitors, notch receptor inhibitors or Rho-associated coiled-coil protein kinase (ROCK) inhibitors could inhibit EMT in differentiated epithelial cells or could induce MET in dedifferentiated epithelial cells [84]. The metanephric mesenchyme suffers an epithelial transformation regulated by WNT4 [85]. During this transformation, the WNT4 signal can be replaced by other members of the WNT gene family, including WNT1, WNT3A, WNT7A and WNT7B [86]. WNT proteins are also involved in cardiac development and differentiation [87]. The classic canonical WNT signaling pathway involves \(\beta\)-catenin [87].