HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
| Autor: | Manuela Völkner, Felix Wagner, Lisa Maria Steinheuer, Madalena Carido, Thomas Kurth, Ali Yazbeck, Jana Schor, Stephanie Wieneke, Lynn J. A. Ebner, Claudia Del Toro Runzer, David Taborsky, Katja Zoschke, Marlen Vogt, Sebastian Canzler, Andreas Hermann, Shahryar Khattak, Jörg Hackermüller, Mike O. Karl |
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| Rok vydání: | 2020 |
| Předmět: |
pathology [Organoids]
Multidisciplinary General Physics and Astronomy General Chemistry Actomyosin HBEGF protein human General Biochemistry Genetics and Molecular Biology Ion Channels Retina pathology [Retina] Organoids Macular Degeneration Tumor Necrosis Factors PIEZO1 protein human Humans Photoreceptor Cells ddc:500 pathology [Macular Degeneration] Heparin-binding EGF-like Growth Factor |
| Zdroj: | Nature Communications 13(1), 6183 (2022). doi:10.1038/s41467-022-33848-y |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-022-33848-y |
| Popis: | Human organoids could facilitate research of complex and currently incurable neuropathologies, such as age-related macular degeneration (AMD) which causes blindness. Here, we establish a human retinal organoid system reproducing several parameters of the human retina, including some within the macula, to model a complex combination of photoreceptor and glial pathologies. We show that combined application of TNF and HBEGF, factors associated with neuropathologies, is sufficient to induce photoreceptor degeneration, glial pathologies, dyslamination, and scar formation: These develop simultaneously and progressively as one complex phenotype. Histologic, transcriptome, live-imaging, and mechanistic studies reveal a previously unknown pathomechanism: Photoreceptor neurodegeneration via cell extrusion. This could be relevant for aging, AMD, and some inherited diseases. Pharmacological inhibitors of the mechanosensor PIEZO1, MAPK, and actomyosin each avert pathogenesis; a PIEZO1 activator induces photoreceptor extrusion. Our model offers mechanistic insights, hypotheses for neuropathologies, and it could be used to develop therapies to prevent vision loss or to regenerate the retina in patients suffering from AMD and other diseases. |
| Databáze: | OpenAIRE |
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