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

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.

SUBMITTER: Volkner M

PROVIDER: S-EPMC9581928 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Völkner Manuela M Wagner Felix F Steinheuer Lisa Maria LM Carido Madalena M Kurth Thomas T Yazbeck Ali A Schor Jana J Wieneke Stephanie S Ebner Lynn J A LJA Del Toro Runzer Claudia C Taborsky David D Zoschke Katja K Vogt Marlen M Canzler Sebastian S Hermann Andreas A Khattak Shahryar S Hackermüller Jörg J Karl Mike O MO

Nature communications 20221019 1

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 photorec ...[more]

PMID: 36261438

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Project description:Methods: Profiles of individual human retinal organoids (HRO) at 150, 200 and 250 days of development days were treated for 10 days with HBEGF and TNF, and compared to solvent controls (CTRL). N=6 HROs per timepoint and variable. Single-end sequencing with 30 Mio reads per sample was performed at a length of 75 bases on HiSeq2500 (Illumina). The sequence reads that passed quality filters were analyzed at the transcripts level. Results: Our data independently confirms that this protocol provides HROs with macular-like characteristics and shows low baseline variabilities for rods, cones and Müller glia. These features might be key for disease modeling, since most animal models lack a macula, and most other organoid protocols have low cone cell numbers. We found a significant reduction in the number of rod and cone photoreceptor cells after 10 days after HBEGF-TNF (HT) treatment. Specifically, some photoreceptors show pathologic changes, and some are apically displaced, with their nuclei protruding into or passing out of the retina. Histopathologic changes indicate photoreceptor extrusion of viable or dying cones and rods as a pathomechanism. Notably, photoreceptor displacement through the apical retinal border, and thus ectopy in the region of photoreceptor inner and outer segments, has been described in patients and animal models. In controls, photoreceptors were highly ordered, interspersed and interconnected with each other and with Müller glia processes, and these cell connections make up the outer limiting membrane. Upon HT, glial processes expanded in size, extended laterally along the retinal circumference, and replaced or covered photoreceptors over large areas – forming a seal-like glial scar. Taken together, HT induces photoreceptor degeneration via cell extrusion in conjunction with reactive gliosis, glial proliferation, retinal thickening/dyslamination, and glial seal-like scar formation, which reproduces a complex outer retinal atrophy. Interestingly, our transcriptome data revealed distinct gene expression patterns supporting our histological phenotype, specifically, cone and rod degeneration, reactive gliosis, glial proliferation, and photoreceptor cell extrusion. Conclusions: We show that combined application of HBEGF and TNF, two neuropathology associated factors, is sufficient to induce a complex human retinal pathology. We discovered cone and rod cell extrusion as a pathomechanism for photoreceptor degeneration and a potential interrelationship with glial pathologies. Pharmacological inhibitor experiments support this, and PIEZO1 and MAPK signaling as untapped therapeutic targets, even for complex pathologies. Thus, our model provides mechanistic access to several pathologic processes as well as pathogenic functions of inflammation and biomechanics.

Dataset Information

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

Publications

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

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