Alshehri, Ashwak Hassan M;
(2025)
A study of the synaptogenic potential of human pluripotent stem cell-derived photoreceptor cells for retinal repair.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Due to the non-regenerative nature of the retina, damage to retinal cells is irreversible. In retinitis pigmentosa (RP), progressive retinal photoreceptor loss and the eventual loss of vision are permanent and incurable. Late-stage RP is an ideal target for photoreceptor cell replacement therapy. With recent advances in the generation of stem cell-derived retinal organoids and enrichment of the photoreceptor population, an important next step is to study their integration within the host retina using genetic animal models of RP. Several studies have confirmed that photoreceptors can survive after delivery into the host retina. However, more evidence is required to demonstrate donor-host connectivity post-transplantation. This thesis investigated whether modification of the extracellular environment of donor photoreceptor cells promotes neuritogenesis and synaptogenesis. Human pluripotent stem cell (hPSC)-derived retinal organoids were cultured as a source of retinal cells and an NRL-GFP rod photoreceptor reporter transgene was used to isolate rod photoreceptor cells. Scaffolds and molecules were investigated to promote donor photoreceptor neurite formation and maturation. Hyaluronic acid (HA) hydrogel and the neural cell adhesion molecule (NCAM) were shown to promote photoreceptor neurite sprouting in vitro, in addition to the expression of synapse markers. HA hydrogel-encapsulated cells transplanted subretinally survived with donor cells integrating into the host retinal layers in vivo. When HA hydrogel-NCAM encapsulated photoreceptors were transplanted onto retinal degeneration model retina (rd1) explants, contact via extended neurites was observed between donor hPSC photoreceptors and the host second-order neurons of the murine retina. These findings suggest that the addition of connectivity-promoting molecules to modulate the host retinal environment is a promising avenue for the advancement of photoreceptor replacement therapy. By optimising the synaptogenic potential of transplanted hPSC-derived photoreceptors, it may be possible to restore retinal function and electrophysiological activity to the degenerated retina.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | A study of the synaptogenic potential of human pluripotent stem cell-derived photoreceptor cells for retinal repair |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Human pluripotent stem cells (hPSC), Hyaluronic acid hydrogel, Neural cell adhesion molecule (NCAM), Photoreceptor transplantation, Retinal degeneration, Synaptogenesis |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10206322 |
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