Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice.
Jonathan R SoucyEmil KriukovJulia OswaldJohn MaslandChris PernstichPetr BaranovPublished in: bioRxiv : the preprint server for biology (2024)
Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Traditional RGC transplantation has been limited by poor survival rates of transplanted cells in the hostile microenvironment of a diseased retina. Our research identifies brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) as key elements in retinal development and RGC survival through in silico analysis of the single-cell transcriptome of developing human retinas. Although these factors are abundant during development, they diminish in adulthood. Here, we demonstrate that a slow-release formulation of BDNF and GDNF enhances RGC differentiation and survival in vitro and improves RGC transplantation outcomes in mouse models. This co-treatment increased survival and coverage of donor RGCs within the retina and enhanced neurite extension toward the optic nerve head. Lastly, this co-treatment showed neuroprotective effects on host RGCs, preserving retinal function in a model of optic neuropathy. Altogether, our findings suggest that manipulating the retinal microenvironment with slow-release neurotrophic factors holds promise in regenerative medicine for treating glaucoma and other optic neuropathies. This approach not only improves donor cell survival and integration but also provides a neuroprotective benefit to host cells, indicating a significant advancement for glaucoma therapies.
Keyphrases
- optic nerve
- optical coherence tomography
- induced apoptosis
- cell cycle arrest
- stem cells
- single cell
- diabetic retinopathy
- endothelial cells
- endoplasmic reticulum stress
- mesenchymal stem cells
- genome wide
- depressive symptoms
- cell therapy
- machine learning
- spinal cord injury
- drug delivery
- cell proliferation
- mouse model
- skeletal muscle
- type diabetes
- high throughput
- cerebral ischemia
- weight loss
- insulin resistance
- health insurance
- replacement therapy
- smoking cessation