Host-Graft Synapses Form Functional Microstructures and Shape the Host Light Responses After Stem Cell-Derived...

Area of Science:

• Ophthalmology
• Regenerative Medicine
• Neuroscience

Background:

• Retinitis pigmentosa is a leading cause of blindness with no established treatments.
• Stem cell-derived retinal organoids (SC-ROs) show promise for retinal repair.
• The microstructural details and functional impact of SC-RO derived synapses are not fully understood.

Purpose of the Study:

• To elucidate the microstructures of host-graft synapses formed after SC-RO transplantation.
• To investigate the distribution and functional contribution of these synapses to host retinal light responses.

Main Methods:

• Utilized a reporter system in mouse SC-ROs and rd1 mice (a model for retinal degeneration).
• Employed correlative array tomography to visualize host-graft synapse microstructure.
• Developed a semi-automated algorithm to detect photoreceptor synapses in flat-mount retinas.
• Integrated synapse distribution data with multi-electrode array recordings of light responses.

Main Results:

• Host-graft synapses were found to recapitulate developmental synapse formation, involving horizontal and rod bipolar cells.
• A positive correlation was observed between the density of host-graft synapses and the number of light-responsive host retinal ganglion cells.

Conclusions:

• De novo host-graft synapses replicate the developmental microstructural characteristics of photoreceptor synapses.
• The formation of these synapses significantly contributes to restored light responsiveness following SC-RO transplantation.