HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids

Manuela Völkner, Felix Wagner, Lisa Maria Steinheuer, Madalena Carido, Thomas Kurth, Ali Yazbeck, Jana Schor, Stephanie Wieneke, Lynn J. A. Ebner, Claudia Toro Runzer, David Taborsky, Katja Zoschke, Marlen Vogt, Sebastian Canzler, Andreas Hermann, Shahryar Khattak, Jörg Hackermüller and Mike O. Karl ()
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Manuela Völkner: Technische Universität Dresden
Felix Wagner: Technische Universität Dresden
Lisa Maria Steinheuer: Helmholtz Centre for Environmental Research—UFZ
Madalena Carido: Technische Universität Dresden
Thomas Kurth: Technology Platform Core Facility Electron Microscopy and Histology
Ali Yazbeck: Helmholtz Centre for Environmental Research—UFZ
Jana Schor: Helmholtz Centre for Environmental Research—UFZ
Stephanie Wieneke: German Center for Neurodegenerative Diseases (DZNE) Dresden
Lynn J. A. Ebner: German Center for Neurodegenerative Diseases (DZNE) Dresden
Claudia Toro Runzer: German Center for Neurodegenerative Diseases (DZNE) Dresden
David Taborsky: German Center for Neurodegenerative Diseases (DZNE) Dresden
Katja Zoschke: German Center for Neurodegenerative Diseases (DZNE) Dresden
Marlen Vogt: Technische Universität Dresden
Sebastian Canzler: Helmholtz Centre for Environmental Research—UFZ
Andreas Hermann: Technische Universität Dresden
Shahryar Khattak: Technische Universität Dresden
Jörg Hackermüller: Helmholtz Centre for Environmental Research—UFZ
Mike O. Karl: Technische Universität Dresden

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33848-y

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