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Updated: Dec 25, 2025
Performing Subretinal Injections in Rodents to Deliver Retinal Pigment Epithelium Cells in Suspension
Published on: January 23, 2015
Paracrine effects of intraocularly implanted cells on degenerating retinas in mice
Xiao Liu1,2, Fenghua Chen1,3, Yao Chen1,4
1Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E Muhammad Ali Blvd, Louisville, KY, 40202, USA.
Background:
Retinal degeneration is a leading cause of blindness in the world; its etiology is complex and involves genetic defects and stress-associated aging. In addition to gene therapies for known genetically defective retinal degeneration, cellular therapies have been widely explored for restoring vision in both preclinical animal models and clinical trials. Stem cells of distinct tissue sources and their derived lineages have been tested for treating retinal degeneration; most of them were reported to be effective to some extent in restoring/improving deteriorated vision. Whether this visual improvement is due to a functional integration of grafted cells to substitute for lost retinal neurons in recipients or due to their neuroprotective and neurotrophic effects to retain recipient functional neurons, or both, is still under debate.
Methods:
We compared the results of subretinal transplantation of various somatic cell types, such as stem cells and differentiated cells, into RhoP23H/+ mice, a retinal degeneration model for human retinitis pigmentosa (RP) by evaluating their optokinetic response (OKR) and retinal histology. We identified some paracrine factors in the media that cultured cells secreted by western blotting (WB) and functionally evaluated the vascular endothelial growth factor Vegfa for its potential neurotrophic and neuroprotective effects on the neuroretina of model animals by intravitreal injection of VEGF antibody.
Results:
We found that live cells, regardless of whether they were stem cells or differentiated cell types, had a positive effect on improving degenerating retinas after subretinal transplantation; the efficacy depended on their survival duration in the host tissue. A few paracrine factors were identified in cell culture media; Vegfa was the most relevant neurotrophic and neuroprotective factor identified by our experiments to extend neuron survival duration in vivo.
Conclusions:
Cellular therapy-produced benefits for remediating retinal degeneration are mostly, if not completely, due to a paracrine effect of implanted cells on the remaining host retinal neurons.
Insights
Cellular therapy improves vision in retinal degeneration models by releasing beneficial factors, not by replacing lost cells. Vascular endothelial growth factor (Vegfa) is key for neuron survival and visual recovery.
Area of Science:
- Ophthalmology
- Regenerative Medicine
- Neuroscience
Background:
- Retinal degeneration causes significant vision loss globally, with complex genetic and aging-related factors.
- Cellular therapies, using various stem and differentiated cells, are explored for vision restoration in retinal degeneration.
- The mechanism of visual improvement in cellular therapy (cell integration vs. paracrine effects) remains debated.
Purpose of the Study:
- To compare the efficacy of different somatic cell types in subretinal transplantation for treating retinal degeneration.
- To identify paracrine factors responsible for therapeutic benefits in cellular therapy for retinal degeneration.
- To evaluate the neurotrophic and neuroprotective role of vascular endothelial growth factor (Vegfa) in retinal degeneration.
Main Methods:
- Subretinal transplantation of various somatic cell types into RhoP23H/+ mice, a model for retinitis pigmentosa.
- Evaluation of therapeutic effects using optokinetic response (OKR) and retinal histology.
- Identification of secreted paracrine factors via western blotting and functional assessment of Vegfa's role.
Main Results:
- All transplanted live cell types, including stem and differentiated cells, improved retinal degeneration.
- Therapeutic efficacy correlated with the survival duration of transplanted cells in the host retina.
- Vascular endothelial growth factor (Vegfa) was identified as a key paracrine factor promoting neuron survival in vivo.
Conclusions:
- The benefits of cellular therapy for retinal degeneration primarily stem from paracrine effects on host retinal neurons.
- Implanted cells do not need to integrate functionally to provide therapeutic benefits.
- Paracrine factors, particularly Vegfa, are crucial for extending neuron survival and improving vision.
