Transfer of cell material by photoreceptor transplantation: mechanisms and implications on therapy development
Final Report Abstract
Cell-based strategies for the treatment of photoreceptors of currently incurable retinal degenerative diseases are under intensive investigation. While photoreceptor transplantation for the replacement of lost cells has been the main direction for potential cell therapies, the finding of material transfer between donor and host photoreceptors represents a novel approach for therapy development. Indeed, the findings of our and other studies provide strong evidence for the formation of tunnelling nanotubes between cells that appear to be highly specialized for photoreceptors adding further communication channels between cells. Interestingly, such cellular bridges appear not to be restricted to a transplantation setting, but were also detected between cone and rod photoreceptors in the normal, unaffected mammalian retina. This observation opens new directions in studying and understanding cellcell interactions and visual processing in the retina. Indeed, our results show that proteins as well as mRNA can be transferred between photoreceptors pointing to the possibility that diverse bio-active molecules can be exchanged between cells. This opens the interesting perspective that transplanted donor photoreceptors can deliver and modify “diseased” photoreceptors at a larger, multi-factorial scale than e.g. supplementation by gene therapy via AAVs, as these will allow the expression of only a single gene/protein. However, more studies have to be conducted to decipher the mechanism, extent, directionality and functional implications of transferred cytoplasmic material between mammalian photoreceptors und physiological as well as pathological conditions. The development of therapies for functional repair via photoreceptor transplantation might therefore follow two routes: (1) replacement of lost photoreceptors in severely degenerated retinas where the majority of photoreceptors have been lost (cell replacement therapy), or (2) transfer of cytoplasmic material from donor to host photoreceptors in conditions, where endogenous photoreceptors are dysfunctional but still existing (cell support therapy).
Publications
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(2019) Restoration of visual function by transplantation of optogenetically engineered photoreceptors. Nat Commun, 10(1):4524
Garita-Hernandez M, Lampič M, Chaffiol A, Guibbal L, Routet F, Santos-Ferreira T, Gasparini S, Borsch O, Gagliardi G, Reichman S, Picaud S, Sahel JA, Goureau O, Ader A, Dalkara D, Duebel J
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(2019) Rod nuclear architecture determines contrast transmission of the retina and behavioral sensitivityin mice. ELife, 8. pii: e49542
Subramanian K, Weigert M, Borsch O, Petzold H, Garcia-Ulloa A, Myers EW, Ader M, Solovei I, Kreysing M
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(2019) Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. Prog Eye Retin Res, 69:1-37
Gasparini SJ, Llonch S, Borsch O, Ader M
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(2022) Evidence for endogenous exchange of cytoplasmic material between a subset of cone and rod photoreceptors within the adult mammalian retina via direct cell-cell connections. Exp Eye Res, 11:109033
Heisterkamp P, Borsch O, Lezama ND, Gasparini S, Fathima A, Carvalho LS, Wagner F, Karl MO, Schlierf M, Ader M
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(2023). Micromanipulator-Assisted Subretinal Transplantation of Human Photoreceptor Reporter Cell Suspensions into Mice. In: Gopalakrishnan J (eds) Brain Organoid Research. Neuromethods, vol 189. Humana, New York, NY
Tessmer K, Borsch O, Ader M, Gasparini SJ
