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Title (Primary) HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Author Völkner, M.; Wagner, F.; Steinheuer, L.M.; Carido, M.; Kurth, T.; Yazbeck, A.; Schor, J.; Wieneke, S.; Ebner, L.J.A.; Del Toro Runzer, C.; Taborsky, D.; Zoschke, K.; Vogt, M.; Canzler, S.; Hermann, A.; Khattak, S.; Hackermüller, J.; Karl, M.O.
Journal Nature Communications
Year 2022
Department MOLSYB; BIOINF
Volume 13
Page From art. 6183
Language englisch
Topic T9 Healthy Planet
Data links https://doi.org/10.5281/zenodo.5188650
Supplements https://www.nature.com/articles/s41467-022-33848-y#Sec43
Abstract 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.
Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=26754
Völkner, M., Wagner, F., Steinheuer, L.M., Carido, M., Kurth, T., Yazbeck, A., Schor, J., Wieneke, S., Ebner, L.J.A., Del Toro Runzer, C., Taborsky, D., Zoschke, K., Vogt, M., Canzler, S., Hermann, A., Khattak, S., Hackermüller, J., Karl, M.O. (2022):
HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Nat. Commun. 13 , art. 6183