Fig. 10: Summary: HT-HRO model phenotype, mechanism, and potential relation to retinal pathologies.
a Scheme of the HBEGF-TNF (HT)-induced pathology model in human retinal organoids (HT-HRO): several distinct histopathologic processes progressively develop in a spatiotemporally-combined and quantifiable manner. Cone and rod photoreceptor (PR) degeneration via apical cell displacement (ectopy) out of the retina with subsequent cell death, combined with several Müller glia (MG) pathologies, is one complex phenotype. (Ultra)structural, molecular, and functional pharmacological inhibitor data indicate a mechanism: (b) HT application or PIEZO1 activation induces PR degeneration via cell extrusion with or without extensive glial pathologies, respectively. Inhibition of MAPK (UO126), PIEZO1 (GsMTx4), or actin-myosin (BLEB, Blebbistatin) signaling each effectively prevents not only PR extrusion but also the complex phenotype. c Summary scheme depicting healthy human retina and selected pathologic processes potentially relevant for AMD and other pathologies, and d, e potential sources and functions of TNF, HBEGF (EGF may have a similar effect), and biomechanical stress in retinal pathologies (indicated in red and numbered) as a basis to discuss and speculate about the potential relevance of the pathologic processes reproduced in the HT-HRO model for patients. Some key hypotheses: PR degeneration by extrusion might underlie PR displacement (white arrow), possibly associated with aging, advanced AMD, and some other pathologies. PIS loss (PISL) is a hallmark of definitive and irreversible vision loss, which might cause or be a consequence of PR extrusion and scarring. Glial scar formation might cause/contribute to PR extrusion, and complex or endstage retinal pathologies. Pathologies might induce HT from various sources (numbered), including retinal cells, microglia, or systemically, and changes in retinal structure or biophysical cell or tissue properties, e.g., due to extracellular pathologic material or changes in choroid/RPE. e See Supplementary Data 1. Image legend: (1) Müller glia; (2) PR; (3) PR inner segments (PIS); (4) microglia; (5) RPE, retinal pigment epithelium; (6) extruding RPE; (7) systemic/entire body; (8) SDD, subretinal drusenoid deposits (extracellular pathologic material between retina and RPE), which might result from extruded photoreceptors13,48,61 (white arrows); and (9) D, Drusen (extracellular pathologic material below the RPE). BM Bruch’s membrane, OLM outer-limiting membrane.
