Home > Publications Database > HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids. > print

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100 1 _ |a Völkner, Manuela
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245 _ _ |a HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids.
260 _ _ |a [London]
|c 2022
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 7 |a Actomyosin
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650 _ 7 |a HBEGF protein, human
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650 _ 7 |a Heparin-binding EGF-like Growth Factor
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650 _ 7 |a Ion Channels
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650 _ 7 |a PIEZO1 protein, human
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650 _ 7 |a Tumor Necrosis Factors
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Actomyosin
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650 _ 2 |a Heparin-binding EGF-like Growth Factor
|2 MeSH
650 _ 2 |a Ion Channels
|2 MeSH
650 _ 2 |a Macular Degeneration: pathology
|2 MeSH
650 _ 2 |a Organoids: pathology
|2 MeSH
650 _ 2 |a Photoreceptor Cells
|2 MeSH
650 _ 2 |a Retina: pathology
|2 MeSH
650 _ 2 |a Tumor Necrosis Factors
|2 MeSH
700 1 _ |a Wagner, Felix
|0 P:(DE-2719)2811441
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700 1 _ |a Steinheuer, Lisa Maria
|0 0000-0002-2329-801X
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700 1 _ |a Carido, Madalena
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700 1 _ |a Kurth, Thomas
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700 1 _ |a Yazbeck, Ali
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700 1 _ |a Schor, Jana
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700 1 _ |a Wieneke, Stephanie
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700 1 _ |a Ebner, Lynn
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700 1 _ |a Del Toro Runzer, Claudia
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700 1 _ |a Taborsky, David
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700 1 _ |a Zoschke, Katja
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700 1 _ |a Vogt, Marlen
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700 1 _ |a Canzler, Sebastian
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700 1 _ |a Hermann, Andreas
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700 1 _ |a Khattak, Shahryar
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700 1 _ |a Hackermüller, Jörg
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700 1 _ |a Karl, Mike Oliver
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773 _ _ |a 10.1038/s41467-022-33848-y
|g Vol. 13, no. 1, p. 6183
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|x 2041-1723
856 4 _ |u https://pub.dzne.de/record/165373/files/DZNE-2022-01647.pdf
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