At three places in
Figure 1, RPE cells attain different morphologies and different functional repertoires, including even migration (‘Dissociated’ to ‘Subducted,’ ‘Entombed’ to ‘Melanotic,’ and ‘Sloughed’ to ‘Intraretinal’). It remains to be determined whether the cells in question are displaced and/or partially degenerated RPE that assumed different morphology but still retained their essential nature. Despite this uncertainty, it is tempting to revisit the hypothesis that in AMD, RPE undergoes transdifferentiation,
10,11 the process by which one differentiated cell type transforms to another cell type. Epithelium-to-mesenchymal transition is a well-studied exemplar transdifferentiation process in which a polarized epithelial cell on its basement membrane responds to its environment with loss of polarity, enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and increased production of extracellular matrix components. When EMT is complete, basement membrane degrades, and a mesenchymal cell migrates away from its layer of origin.
9,42,43 Key molecular events are de novo expression of α-smooth muscle actin, upregulation of the intermediate filament vimentin, and concomitant repression of cytokeratin. These events occur in RPE adopting contractile behavior in culture,
10 in RPE surgically excised from patients with proliferative vitreoretinopathy and neovascular AMD,
11,44 and in ‘Sloughed’ and ‘Intraretinal’ RPE from AMD eyes.
12 Immunoreactivity for α-smooth muscle actin
12 and the transmembrane protein CX3CR1
24 localizes to flat profiles on BrM consistent with ‘Subducted’ cells, yet not exhibiting RPE granules; these suggestive results should be revisited with higher-resolution labeling studies. Oncogenic EMT is further associated with defects in key tumor suppressors, including phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a potent activator of the phosphoinositide 3-kinase signaling cascade.
45 In mice, this gene product strongly and preferentially localizes to basolateral RPE, relative to other retinal layers.
46 The PTEN-deficient RPE loses intercellular adhesions, upregulates motility genes, undergoes EMT, and migrates completely out of the eye.
46 These startling results suggest that under appropriate circumstances, RPE in vivo readily becomes migratory, due to an intrinsic motility that is normally countered within the epithelial layer by PTEN. We considered EMT because it is well characterized molecularly and because evidence currently exists for RPE, yet we emphasize that determining whether transdifferentiation is operative in AMD and how it takes place awaits new research.