Cardiomyocyte Transdifferentiation

In addition to the pale cytoplasmic plaque of the mechanical junction, vacuoles, numerous Golgi profiles, and giant lipid droplets in some cardiomyocytes are characteristic features of ARVC/D (Fig. 6.1c).

Lipid droplets inside cardiomyocytes were documented by Masani et al. [37] and D'Amati et al. [38]. D'Amati et al. combined this observation with im-munohistochemical finding of vimentin and interpreted it as a feature of cardiomyocyte transdifferentiation into adipocytes. Transdifferentiation of my-oblasts, fibroblasts, and osteoblasts into adipocytes has been reported [39,40]. Absence of the Wnts signal, overexpression of peroxisome proliferator-acti-vated receptor-gamma (PPARy), and degradation of P-catenin play a key role during transdifferentiation [41,42]. Pale cytoplasmic plaques of fascia adherens in cardiomyocytes of ARVC/D hearts might be a feature of their defective protein composition, including P-catenin. It is also possible that the presence of numerous Golgi profiles and vacuoles are related to abnormally activated recirculation and degradation of P-catenin, respectively.

Recently, Garcia-Gras et al. [43] demonstrated that cardiac-specific loss of the desmosomal protein desmoplakin can cause nuclear translocation of plakoglobin, upregulation of adipogenic and fi-brogenic genes in vitro (by reduction in canonical Wnt/beta-catenin signaling). The Authors did not identify the cell source of excessive adipocytes in the heart, but state that they are likely to be com posed of cardiac myoblasts or resident and circulating mesenchimal stem cells. In the absence of Wnt signaling, this could preferentially differentiate into adipocytes. Alternatively, the source could be fibrocytes, which are considered adipocyte progenitor cells. This view is further supported by the regular presence of adipocytes and fibrosis in the myocardium of patients with ARVC/D as well as in the hearts of desmoplakin-deficient mice. Although no ultrastructural investigation was carried out in their model, they provided histologic evidence of extensive areas of fibroadipocytic replacement of myocytes, accumulation of fat droplets predominantly at the site of fibrosis seen on oil red stained myocardial sections and increased myocyte apop-tosis.

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