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@ARTICLE{Vlkner:165373,
      author       = {Völkner, Manuela and Wagner, Felix and Steinheuer, Lisa
                      Maria and Carido, Madalena and Kurth, Thomas and Yazbeck,
                      Ali and Schor, Jana and Wieneke, Stephanie and Ebner, Lynn
                      and Del Toro Runzer, Claudia and Taborsky, David and
                      Zoschke, Katja and Vogt, Marlen and Canzler, Sebastian and
                      Hermann, Andreas and Khattak, Shahryar and Hackermüller,
                      Jörg and Karl, Mike Oliver},
      title        = {{HBEGF}-{TNF} induce a complex outer retinal pathology with
                      photoreceptor cell extrusion in human organoids.},
      journal      = {Nature Communications},
      volume       = {13},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2022-01647},
      pages        = {6183},
      year         = {2022},
      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.},
      keywords     = {Humans / Actomyosin / Heparin-binding EGF-like Growth
                      Factor / Ion Channels / Macular Degeneration: pathology /
                      Organoids: pathology / Photoreceptor Cells / Retina:
                      pathology / Tumor Necrosis Factors / Actomyosin (NLM
                      Chemicals) / HBEGF protein, human (NLM Chemicals) /
                      Heparin-binding EGF-like Growth Factor (NLM Chemicals) / Ion
                      Channels (NLM Chemicals) / PIEZO1 protein, human (NLM
                      Chemicals) / Tumor Necrosis Factors (NLM Chemicals)},
      cin          = {AG Karl / Cell culture platform / AG Hermann},
      ddc          = {500},
      cid          = {I:(DE-2719)1710004 / I:(DE-2719)1740003 /
                      I:(DE-2719)1511100},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36261438},
      pmc          = {pmc:PMC9581928},
      doi          = {10.1038/s41467-022-33848-y},
      url          = {https://pub.dzne.de/record/165373},
}