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

Author

Listed:
  • Manuela Völkner

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Felix Wagner

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) 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
    German Center for Neurodegenerative Diseases (DZNE) Dresden
    Technische Universität Dresden)

  • Shahryar Khattak

    (Technische Universität Dresden
    Technology Platform Core Facility Electron Microscopy and Histology)

  • Jörg Hackermüller

    (Helmholtz Centre for Environmental Research—UFZ
    Leipzig University)

  • Mike O. Karl

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) Dresden)

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.

Suggested Citation

  • 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, 2022. "HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33848-y
    DOI: 10.1038/s41467-022-33848-y
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    References listed on IDEAS

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    1. Madhvi Menon & Shahin Mohammadi & Jose Davila-Velderrain & Brittany A. Goods & Tanina D. Cadwell & Yu Xing & Anat Stemmer-Rachamimov & Alex K. Shalek & John Christopher Love & Manolis Kellis & Brian P, 2019. "Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    2. Christine Wolf & Alexander Rapp & Nicole Berndt & Wolfgang Staroske & Max Schuster & Manuela Dobrick-Mattheuer & Stefanie Kretschmer & Nadja König & Thomas Kurth & Dagmar Wieczorek & Karin Kast & M. C, 2016. "RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    3. S. A. Gudipaty & J. Lindblom & P. D. Loftus & M. J. Redd & K. Edes & C. F. Davey & V. Krishnegowda & J. Rosenblatt, 2017. "Mechanical stretch triggers rapid epithelial cell division through Piezo1," Nature, Nature, vol. 543(7643), pages 118-121, March.
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