Abstract
Müller glia (MG) function as injury-induced retinal stem cells in zebrafish but not mammals. Insights from zebrafish, however, have been used to stimulate limited regenerative responses from mammalian MG. Microglia/macrophages regulate MG stem cell activity in the chick, zebrafish and mouse. We previously showed that dexamethasone can accelerate retinal regeneration in zebrafish. Similarly, microglia ablation enhances regenerative outcomes in the mouse retina. Targeted immunomodulation may therefore enhance the regenerative potential of human MG. Nanoparticle-based immunomodulation is an emerging field with immense therapeutic potential. Here, we investigated how regeneration-enhancing dexamethasone treatments alter microglia behavior and how dendrimer-based targeting of dexamethasone to reactive microglia impact retinal regeneration kinetics. Intravital time-lapse imaging revealed specific dexamethasone-induced changes in microglia reactivity. Dendrimer-conjugated dexamethasone treatments resulted in: 1) decreased toxicity, 2) selective targeting of reactive microglia and, 3) “super-accelerated” retinal regeneration kinetics. These data support the use of dendrimer-based drug formulations for modulating microglia reactivity in degenerative disease contexts, especially as therapeutic strategies for promoting regenerative responses to neuronal cell loss.
Competing Interest Statement
JSM holds patents for the NTR inducible cell ablation system (US #7,514,595) and uses thereof (US #8,071,838 and US#8431768). RMK and SPK have awarded and pending patents relating to the hydroxyl dendrimer platform for ocular therapies. RMK and his wife (Sujatha Kannan) are co-founders/board members, and have financial interests in Ashvattha Therapeutics Inc., a start-up focusing on clinical translation of the dendrimer platform.
Footnotes
↵* Co-first author
Clarified author order