Characterization of an acute murine model of retinal degeneration for photoreceptor transplantation

Ph.D. Rodrigo Ramos Acevedo

AutorIn

Ph.D. Rodrigo Ramos Acevedo

Titel

Characterization of an acute murine model of retinal degeneration for photoreceptor transplantation

Zitierfähige Url:

https://nbn-resolving.org/urn:nbn:de:bsz:14-qucosa2-1032306

Erstveröffentlichung

2026

Datum der Einreichung

08.09.2025

Datum der Verteidigung

25.02.2026

Abstract (EN)

Retinal degenerative diseases present progressive photoreceptor death and retinal remodeling that leads to loss of sight. Several treatments exist, and are aimed at stopping the advance of the degeneration by reducing oxidative stress or neovascularization, but lost photoreceptors do not regenerate. Moreover, current animal models fall short in portraying the complexity of these diseases, limiting our ability to understand the pathological mechanisms that lead to cell death and possibly develop therapies that could reestablish sight. To further study retinal degeneration across different systems, the Karl lab showed that the combination of the cytokines HBEGF and TNF-alpha (HT) induced complex retinal pathology in mouse and human retinal organoids, mouse retinal explants, and eyes of postnatal mice. Nonetheless, these models have limitations in comparison with an adult in vivo system in which the complexity of the phenotype and its systemic effects can be studied in depth. Thus, to tackle degeneration in the retina, cell replacement strategies aim to substitute degenerated photoreceptors by transplanting new cells into the retina. It has been observed, however, that the survival and differentiation of transplanted photoreceptors vary according to the local microenvironment. Moreover, it has been proposed that a severely degenerated retina would not be able to sustain transplanted photoreceptors, as the damaged photoreceptor layer might be required for cells to incorporate. Here, we wanted to evaluate whether the HT-treatment could induce in adult mice the complex retinal pathology phenotype and if the HT-induced degeneration would be able to sustain transplanted photoreceptors derived from human retinal organoids. We found that the combination of the HT cytokines produced a dose-dependent, complex retinal pathology phenotype, similar to what was shown in vitro and ex vivo, which included photoreceptor death, Müller glia reactivity, retinal folding, and cell ectopy for up to 30 days after the HT injection. When HT-treated eyes were transplanted, we observed that grafted photoreceptors survive and present more interactions with the host in the HT-treated group than in the Sham condition shortly after transplantation. Six months after transplantation, second-order neurons presented interactions with grafted cells in both conditions. Thus, this thesis proposes a dose-dependent, low-cost model of acute retinal degeneration. Additionally, this model sheds light on the synergic effect that the inflammatory response can produce and its degenerative effects in the retina. Moreover, it also suggests the relevance of activated Müller glia and its role in transplantation survival and development.

Freie Schlagwörter (DE)

Zellersatz, Netzhautdegeneration, Müller-Gliazellen, Netzhautorganoide

Freie Schlagwörter (EN)

Cell replacement, Retinal degeneration, Müller glia, retinal organoids.

Klassifikation (DDC)

610

Klassifikation (RVK)

YO 8104

GutachterIn