Purpose: Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Autologous and allogeneic RGC replacement with stem cell-derived neurons is a promising strategy for vision restoration; however, low (<1%) donor cell survival in the diseased retina and optic nerve remains a major limitation. We aimed to improve initial donor RGC survival by supplementing transplants with slow-release neuroprotective factors.
Methods: Mouse and human stem cell-derived RGCs were cultured and transplanted into mouse models of optic neuropathy with or without a slow-release formulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). Donor RGC differentiation, survival, and function were assessed in vitro using flow cytometry, multielectrode array recordings, and neurite outgrowth analysis. Donor RGC survival and host retinal function after transplantation and BDNF/GDNF co-treatment in mice were evaluated using retinal flat mounts and electroretinography.
Results: Slow-release BDNF/GDNF significantly enhanced RGC differentiation, survival, and spontaneous neural activity in vitro. In vivo, co-treatment improved donor RGC transplantation outcomes by 2.7-fold for mouse RGCs and 15-fold for human RGCs in mice. Additionally, slow-release BDNF/GDNF preserved host RGC function, providing neuroprotection against injury-induced retinal dysfunction.
Conclusions: Engineering the retinal microenvironment with slow-release neurotrophic factors significantly enhances both donor and host neuron survival, representing a promising approach for treating glaucoma and other optic neuropathies.
Translational relevance: This study demonstrates that sustained neurotrophic factor delivery can protect vision and improve retinal neuron transplantation outcomes, advancing the treatment of optic neuropathies at both mild and severe stages.