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000165373 1001_ $$0P:(DE-2719)2810390$$aVölkner, Manuela$$b0$$eFirst author
000165373 245__ $$aHBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids.
000165373 260__ $$a[London]$$bNature Publishing Group UK$$c2022
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000165373 520__ $$aHuman organoids could facilitate research of complex and currently incurable neuropathologies, such as age-related macular degeneration (AMD) which causes blindness. Here, we establish a human retinal organoid system reproducing several parameters of the human retina, including some within the macula, to model a complex combination of photoreceptor and glial pathologies. We show that combined application of TNF and HBEGF, factors associated with neuropathologies, is sufficient to induce photoreceptor degeneration, glial pathologies, dyslamination, and scar formation: These develop simultaneously and progressively as one complex phenotype. Histologic, transcriptome, live-imaging, and mechanistic studies reveal a previously unknown pathomechanism: Photoreceptor neurodegeneration via cell extrusion. This could be relevant for aging, AMD, and some inherited diseases. Pharmacological inhibitors of the mechanosensor PIEZO1, MAPK, and actomyosin each avert pathogenesis; a PIEZO1 activator induces photoreceptor extrusion. Our model offers mechanistic insights, hypotheses for neuropathologies, and it could be used to develop therapies to prevent vision loss or to regenerate the retina in patients suffering from AMD and other diseases.
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000165373 650_7 $$09013-26-7$$2NLM Chemicals$$aActomyosin
000165373 650_7 $$2NLM Chemicals$$aHBEGF protein, human
000165373 650_7 $$2NLM Chemicals$$aHeparin-binding EGF-like Growth Factor
000165373 650_7 $$2NLM Chemicals$$aIon Channels
000165373 650_7 $$2NLM Chemicals$$aPIEZO1 protein, human
000165373 650_7 $$2NLM Chemicals$$aTumor Necrosis Factors
000165373 650_2 $$2MeSH$$aHumans
000165373 650_2 $$2MeSH$$aActomyosin
000165373 650_2 $$2MeSH$$aHeparin-binding EGF-like Growth Factor
000165373 650_2 $$2MeSH$$aIon Channels
000165373 650_2 $$2MeSH$$aMacular Degeneration: pathology
000165373 650_2 $$2MeSH$$aOrganoids: pathology
000165373 650_2 $$2MeSH$$aPhotoreceptor Cells
000165373 650_2 $$2MeSH$$aRetina: pathology
000165373 650_2 $$2MeSH$$aTumor Necrosis Factors
000165373 7001_ $$0P:(DE-2719)2811441$$aWagner, Felix$$b1
000165373 7001_ $$00000-0002-2329-801X$$aSteinheuer, Lisa Maria$$b2
000165373 7001_ $$aCarido, Madalena$$b3
000165373 7001_ $$00000-0001-5624-1717$$aKurth, Thomas$$b4
000165373 7001_ $$aYazbeck, Ali$$b5
000165373 7001_ $$aSchor, Jana$$b6
000165373 7001_ $$0P:(DE-2719)2812103$$aWieneke, Stephanie$$b7
000165373 7001_ $$0P:(DE-2719)2812120$$aEbner, Lynn$$b8
000165373 7001_ $$0P:(DE-2719)2812544$$aDel Toro Runzer, Claudia$$b9
000165373 7001_ $$0P:(DE-2719)9002480$$aTaborsky, David$$b10$$udzne
000165373 7001_ $$0P:(DE-2719)2810521$$aZoschke, Katja$$b11
000165373 7001_ $$0P:(DE-2719)2811798$$aVogt, Marlen$$b12
000165373 7001_ $$00000-0001-7935-9582$$aCanzler, Sebastian$$b13
000165373 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b14
000165373 7001_ $$00000-0003-0580-190X$$aKhattak, Shahryar$$b15
000165373 7001_ $$00000-0003-4920-7072$$aHackermüller, Jörg$$b16
000165373 7001_ $$0P:(DE-2719)2000041$$aKarl, Mike Oliver$$b17$$eLast author
000165373 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-022-33848-y$$gVol. 13, no. 1, p. 6183$$n1$$p6183$$tNature Communications$$v13$$x2041-1723$$y2022
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