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Hippo pathway inhibition restores visual function in blind mice via Müller glia-derived photoreceptor regeneration

ABSTRACT: Photoreceptor loss causes irreversible blindness, with no effective therapies due to the mammalian retina’s inability to regenerate. Extending our previous finding that targeting the core Hippo effector YAP drives limited Müller glia (MG)-to-inner retinal neuron transdifferentiation yet induced marked, transient MG migration toward the outer retina, even in an inner retinal injury model. These results indicate that YAP holds high potential to instruct photoreceptor fate from endogenous MG. Here, we show that Hippo pathway acts as a master regulator governing MG trans-differentiation into photoreceptors. Genetic and pharmacological modulation of YAP promotes MG proliferation and drives their commitment to a photoreceptor lineage in a mouse model of outer nuclear layer injury.A single intravitreal injection of TDI‑011536 delivered via GelMA‑encapsulated mesoporous silica nanoparticles achieves substantial photoreceptor regeneration and restores visual function in blind mice, without systemic toxicity. Our findings identify the Hippo pathway as a promising therapeutic target for photoreceptor degenerative diseases and establish this nanoparticle system as a viable platform for clinical translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE336782 | GEO | 2026/07/31

REPOSITORIES: GEO

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Project description:Methods: Profiles of individual human retinal organoids (HRO) at 150, 200 and 250 days of development days were treated for 10 days with HBEGF and TNF, and compared to solvent controls (CTRL). N=6 HROs per timepoint and variable. Single-end sequencing with 30 Mio reads per sample was performed at a length of 75 bases on HiSeq2500 (Illumina). The sequence reads that passed quality filters were analyzed at the transcripts level. Results: Our data independently confirms that this protocol provides HROs with macular-like characteristics and shows low baseline variabilities for rods, cones and Müller glia. These features might be key for disease modeling, since most animal models lack a macula, and most other organoid protocols have low cone cell numbers. We found a significant reduction in the number of rod and cone photoreceptor cells after 10 days after HBEGF-TNF (HT) treatment. Specifically, some photoreceptors show pathologic changes, and some are apically displaced, with their nuclei protruding into or passing out of the retina. Histopathologic changes indicate photoreceptor extrusion of viable or dying cones and rods as a pathomechanism. Notably, photoreceptor displacement through the apical retinal border, and thus ectopy in the region of photoreceptor inner and outer segments, has been described in patients and animal models. In controls, photoreceptors were highly ordered, interspersed and interconnected with each other and with Müller glia processes, and these cell connections make up the outer limiting membrane. Upon HT, glial processes expanded in size, extended laterally along the retinal circumference, and replaced or covered photoreceptors over large areas – forming a seal-like glial scar. Taken together, HT induces photoreceptor degeneration via cell extrusion in conjunction with reactive gliosis, glial proliferation, retinal thickening/dyslamination, and glial seal-like scar formation, which reproduces a complex outer retinal atrophy. Interestingly, our transcriptome data revealed distinct gene expression patterns supporting our histological phenotype, specifically, cone and rod degeneration, reactive gliosis, glial proliferation, and photoreceptor cell extrusion. Conclusions: We show that combined application of HBEGF and TNF, two neuropathology associated factors, is sufficient to induce a complex human retinal pathology. We discovered cone and rod cell extrusion as a pathomechanism for photoreceptor degeneration and a potential interrelationship with glial pathologies. Pharmacological inhibitor experiments support this, and PIEZO1 and MAPK signaling as untapped therapeutic targets, even for complex pathologies. Thus, our model provides mechanistic access to several pathologic processes as well as pathogenic functions of inflammation and biomechanics.

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Hippo pathway inhibition restores visual function in blind mice via Müller glia-derived photoreceptor regeneration

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