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

Research output: Contribution to journalResearch articleContributedpeer-review



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.


Original languageEnglish
Article number6183
JournalNature communications
Issue number1
Publication statusPublished - 19 Oct 2022

External IDs

Scopus 85140231739
PubMed 36261438
Mendeley 2b26a49e-8b27-399e-91f2-db7626a16a40
ORCID /0000-0001-5624-1717/work/142239051
ORCID /0000-0002-0926-6556/work/142250483


DFG Classification of Subject Areas according to Review Boards

Subject groups, research areas, subject areas according to Destatis

Sustainable Development Goals


  • Humans, Actomyosin, Heparin-binding EGF-like Growth Factor, Ion Channels, Macular Degeneration/pathology, Organoids/pathology, Photoreceptor Cells, Retina/pathology, Tumor Necrosis Factors

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