Journal Article

DZNE-2022-01647

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids.

Völkner, M. (First author)DZNE* ; Wagner, F.DZNE* ; Steinheuer, L. M. ; Carido, M. ; Kurth, T. ; Yazbeck, A. ; Schor, J. ; Wieneke, S.DZNE* ; Ebner, L.DZNE* ; Del Toro Runzer, C.DZNE* ; Taborsky, D.DZNE* ; Zoschke, K.DZNE* ; Vogt, M.Extern* ; Canzler, S. ; Hermann, A.DZNE* ; Khattak, S. ; Hackermüller, J. ; Karl, M. O. (Last author)DZNE*

2022
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-022-33848-y

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.

Keyword(s): Humans (MeSH) ; Actomyosin (MeSH) ; Heparin-binding EGF-like Growth Factor (MeSH) ; Ion Channels (MeSH) ; Macular Degeneration: pathology (MeSH) ; Organoids: pathology (MeSH) ; Photoreceptor Cells (MeSH) ; Retina: pathology (MeSH) ; Tumor Necrosis Factors (MeSH) ; Actomyosin ; HBEGF protein, human ; Heparin-binding EGF-like Growth Factor ; Ion Channels ; PIEZO1 protein, human ; Tumor Necrosis Factors

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Contributing Institute(s):

1. Retinal Regeneration and Degeneration (AG Karl)
2. Cell culture platform (Cell culture platform)
3. Translational Neurodegeneration (AG Hermann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Software Schmied, C.DZNE*
Software: HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids (v1.0.0)
Zenodo (2022) [10.5281/ZENODO.5188650]2022 BibTeX | EndNote: XML, Text | RIS

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Software Wagner, F.DZNE*
Software: Photoreceptor pattern analysis (v1.0.0)
Zenodo (2022) [10.5281/ZENODO.7040860]2022 BibTeX | EndNote: XML, Text | RIS

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