The reversal of retinal degeneration is the central focus of our research activities. Damage to the RPE and progressive destruction of the photoreceptors are critical features of these diseases. Age-related macular degeneration and retinitis pigmentosa are leading causes for vision loss in the industrialized world. So far, no effective treatment to restore the lost vision is available. In order to develop new therapeutical approaches in this regard, we are employing a variety of animal models including zebrafish (ZF) and mouse with induced retinal degeneration. Thereby, pharmacological treatment using cell type-specific toxins (e.g., NaIO3, MNU) and laser-induced damage of the outer nuclear layer are means to induce the pathological changes in the retina. The aim of our experiments is the identification of differences between ZF, a species with high regenerative capacity, and mouse, carrying rather limited regenerative potential, during retinal degeneration/regeneration and how to modulate them towards regeneration. The graphical abstract in Figure 1 shows a summary of developments over in the in the mentioned laser model. The development of a chronic retinal gliosis appears to be a pivotal difference between the investigated species as shown in Figure 2. Thereby, the involvement of Müller cells (depicted as GFAP-positive cells), the main macroglia in the retina, became apparent. Similar development has been found in human samples with pre-AMD morphology (drusen).

Our goal is to optimize endogenous regeneration as this shows enormous potential for future approaches in the retina. We are investigating the employment of Müller cells as potential candidates for replacing degenerated photoreceptors and/or RPE. In this regard, we were able to characterize the different regulation of TGFβ during laser-induced retinal degeneration/regeneration in mouse and ZF (Figure 3). This identifies new target structures to arbitrarily modulate regeneration by activated Müller cells. The inhibition of Smad3, a downstream target of TGF with SIS3 led to a decreased glial scar formation in mice (Figure 4) and might point towards completely new approaches for the treatment of retinal degeneration. Future research will also focus on an active modulation of Müller cell-epithelial transition (MC-ET) as a pivotal process during degeneration/regeneration and the treatment of the chronic gliosis in mice with anti-fibrotic drugs as we found similarities to wound healing (fibrosis).