Extensive incorporation, polarisation and improved maturation of transplanted human cones in a murine cone degeneration model

Once human photoreceptors die, they do not regenerate, thus photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation and synaptic connectivity to the host will be critical in advancing this technology to clinical practice. Unlike the unstructured grafts of prior cell suspension transplantations into end-stage degeneration models, we describe extensive incorporation of iPSC retinal organoid-derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extend throughout the graft, even forming a common outer limiting membrane. Donor-host interaction appears to promote polarisation as well as development of morphological features critical for light detection, namely formation of inner and well stacked outer segments oriented towards the RPE. Putative synapse formation and graft function is evident both at a structural and electrophysiological level. Overall, these results show that human photoreceptors interact readily with a partially degenerated retina. Moreover, incorporation into the host retina appears to be beneficial to graft maturation, polarisation and function.

After-hyperpolarization and receptor potential attenuation following bursts of action potentials in an insect mechanoreceptor

The receptor potential in the sensory neuron of the cockroach femoral tactile spine was recently observed by raising the axon into an oil bath and measuring the decrementally conducted receptor current. Although action potential discharge in this receptor adapts rapidly, there was no evidence of adaptation in the receptor potential. In the present work we report that bursts of action potentials in the neuron produce a prolonged after-hyperpolarization and attenuate the receptor potential. Both of these effects could be important in receptor adaptation and we sought to identify their origin. It was impossible to control ionic concentrations in the fluid surrounding the sensory neuron because of an effective glial barrier, but it was possible to infuse the tissues with chemical agents which are known to block ionic membrane processes. Cobalt and cadmium, which inhibit calcium influx, eliminated the effects of action potentials, and ouabain had similar effects. These results suggest that both a calcium-activated potassium conductance and an electrogenic sodium pump are involved in these phenomena. However, it is argued that the former is probably more important.