Programmed Deletion of Graft Bipolar Cells for Improved Retinal Transplantation

Article: Improved retinal transplant technique ready for clinical trials
Source: RIKEN Center for Biosystems Dynamics Research (Japan)
Published: January 27, 2022

Schematic of wild-type vs. ISL1−/− hESC rat retinas (top),
synaptic complexes in rod (bottom left) and cone (bottom right) bipolar cells

Retinal transplantation has been explored as a treatment option for retinal degenerative conditions such as retinitis pigmentosa and macular degeneration. Transplantation of sheets, or patches, of the retina have been met with graft-host connection challenges, especially with regard to bipolar cells. Connection of graft photoreceptors to host bipolar cells is critical for the transmission of the light signal from the photoreceptors through the bipolar cells and onto the retinal ganglion cells that make up the optic nerve leading to the brain. However, grafted transplant sheets also contain their own bipolar cells. One of the authors explains, "Bipolar cells are inevitably born when the retinal sheet develops properly and photoreceptors mature. But it’s their very connection to the bipolar cells in the retinal sheet that prevents the photoreceptors from connecting to the bipolar cells in the host." In this study, the researchers experimented with genetically modifying bipolar cells (specifically ON-bipolar cells) in the graft retina to die off in the final stages of photoreceptor maturation. Specifically, they used human embryonic stem cells (hESCs) and deleted a gene called Islet-1 (ISL1). The resulting clones were grown into retinal organoid sheets. As hoped, the targeted bipolar cells eventually died off as the retinal sheet developed. When transplanted into rat retinas with end-stage retinal degeneration, the researchers observed that the retinal sheets with the Islet-1 gene deleted (ISL1^−/−) matured properly and made better contact with the host eye, and had better response to light (as measured from downstream retinal ganglion cells) compared to wild-type retinal sheets. From a scientific perspective, the research team was able to observe graft-host synapse formation in the absence of graft bipolar cells, something that was difficult to do before. Finally, the use of human embryonic stem cells in this study brought the technique a big step closer to clinical trials.

My rating of this study: ⭐⭐

Yamasaki S, Tu H, Matsuyama T, et al. "A Genetic modification that reduces ON-bipolar cells in hESC-derived retinas enhances functional integration after transplantation." iScience.  20 December 2021. https://doi.org/10.1016/j.isci.2021.103657