Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

Abstract

Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimics events occurring in human glaucoma. Senescence‐related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence‐associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix‐degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

“…The data that support the findings of this study are openly available in GEO database (GSE141725) and in Dryad at https://doi.org/10.6075/J0707ZTM (Rocha, ).…”

Accelerated aging induced by stress in experimental murine ocular hypertension

“…Interestingly, the core genes within significantly enriched pathways (e.g., inflammatory and apoptosis) were robustly upregulated in 18-month-old animals upon stress whereas only slightly upregulated in young retinas (Figure 2H, Supplementary Figure 2K). Similarly, when we plotted heatmaps for senescence and extracellular matrix deregulation pathways 18 we have observed robust upregulation of the genes in these pathways in 18-month-old IOP-treated retinas but only limited deregulation in 3-monthold-treated retinas. In total, out of 65 top genes dysregulated upon IOP-elevation in 18-month-old retinas, 53 were upregulated more in the old retinas than in the young retinas upon IOP stress (Supplementary Figure 2M).…”

“…In our previous works we have demonstrated that intraocular hypertension of 90 mmHg, non-physiological levels of pressure, induced ∼50% loss of RGCs. 11,18 Therefore, in search of a better system that would mimic the glaucomatous insult, the effects of different levels of IOP elevation on RGC survival were quantified, by unilaterally elevating IOP in 3-month-old C57BL/6J to 30, 50, or 90 mmHg for 1 hour. The contralateral eye served as a healthy sham control.…”

“…We, therefore, hypothesized that we can use a senolytic approach to remove early senescent cells and potentially protect retinal cells from death. Accordingly, we followed a previously established protocol 18 (Figure 2L, top ) , and after unilateral 30mmHg IOP treatment of the retina the animals were intraperitoneally injected daily with a senolytic drug, dasatinib. After 5 days, retinas were collected and immunohistochemistry using anti-Brn3a antibody was performed on IOP treated and non-treated flat-mount retinas.…”

The costs and benefits of senotherapeutics for human health

“…One of the most common chronic neurodegenerative diseases in humans is glaucoma, which is a leading cause of irreversible blindness worldwide. Although a study in a mouse model showed that dasatinib prevented glaucoma-dependent loss of retinal functions and cellular structure, 41 a retrospective study assessing the effects of senolytic drugs on vision in 28 patients with glaucoma showed that senolytic exposure did not affect visual acuity or intraocular pressure, and did not have toxic effects. 74 This pilot study implies that senolytic drugs might not have clinically significant toxicity and, therefore, could be safe for use in humans.…”