HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Article number | 6183 |
Journal | Nature communications |
Volume | 13 |
Issue number | 1 |
Publication status | Published - 19 Oct 2022 |
Peer-reviewed | Yes |
External IDs
Scopus | 85140231739 |
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PubMed | 36261438 |
Mendeley | 2b26a49e-8b27-399e-91f2-db7626a16a40 |
ORCID | /0000-0001-5624-1717/work/142239051 |
ORCID | /0000-0002-0926-6556/work/142250483 |
Keywords
Research priority areas of TU Dresden
DFG Classification of Subject Areas according to Review Boards
Sustainable Development Goals
ASJC Scopus subject areas
Keywords
- Humans, Actomyosin, Heparin-binding EGF-like Growth Factor, Ion Channels, Macular Degeneration/pathology, Organoids/pathology, Photoreceptor Cells, Retina/pathology, Tumor Necrosis Factors