HBEGF-TNF Induce a Complex Outer Retinal Pathology with Photoreceptor Cell Extrusion in Human Organoids

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 19

PMID 36261438

Authors

Manuela Volkner

Felix Wagner

Lisa Maria Steinheuer

Madalena Carido

Thomas Kurth

Ali Yazbeck

Jana Schor

Stephanie Wieneke

Lynn J A Ebner

Claudia Del Toro Runzer

David Taborsky

Katja Zoschke

Marlen Vogt

Sebastian Canzler

Andreas Hermann

Shahryar Khattak

Jorg Hackermuller

Mike O Karl

Affiliations

Soon will be listed here.

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.

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