TY  - JOUR
AU  - Völkner, Manuela
AU  - Wagner, Felix
AU  - Steinheuer, Lisa Maria
AU  - Carido, Madalena
AU  - Kurth, Thomas
AU  - Yazbeck, Ali
AU  - Schor, Jana
AU  - Wieneke, Stephanie
AU  - Ebner, Lynn
AU  - Del Toro Runzer, Claudia
AU  - Taborsky, David
AU  - Zoschke, Katja
AU  - Vogt, Marlen
AU  - Canzler, Sebastian
AU  - Hermann, Andreas
AU  - Khattak, Shahryar
AU  - Hackermüller, Jörg
AU  - Karl, Mike Oliver
TI  - HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids.
JO  - Nature Communications
VL  - 13
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2022-01647
SP  - 6183
PY  - 2022
AB  - 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.
KW  - Humans
KW  - Actomyosin
KW  - Heparin-binding EGF-like Growth Factor
KW  - Ion Channels
KW  - Macular Degeneration: pathology
KW  - Organoids: pathology
KW  - Photoreceptor Cells
KW  - Retina: pathology
KW  - Tumor Necrosis Factors
KW  - Actomyosin (NLM Chemicals)
KW  - HBEGF protein, human (NLM Chemicals)
KW  - Heparin-binding EGF-like Growth Factor (NLM Chemicals)
KW  - Ion Channels (NLM Chemicals)
KW  - PIEZO1 protein, human (NLM Chemicals)
KW  - Tumor Necrosis Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36261438
C2  - pmc:PMC9581928
DO  - DOI:10.1038/s41467-022-33848-y
UR  - https://pub.dzne.de/record/165373
ER  -