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

Lorena Raquel Rocha,Robert N Weinreb,Claudia Palomino La Torre,Viet Anh Nguyen Huu,Dorota Skowronska‐Krawczyk,Mary Jabari,Qianlan Xu,Michal Krawczyk

doi:10.1111/acel.13089

Lorena Raquel Rocha, Robert N Weinreb + Show 6 more

Open Access

https://doi.org/10.1111/acel.13089

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Journal: Aging Cell	Publication Date: Dec 22, 2019
Citations: 47	License type: CC BY 4.0

Affiliation: University of California, San Diego

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.

Highlights

Glaucoma is comprised of progressive optic neuropathies characterized by degeneration of retinal ganglion cells (RGC) and resulting changes in the optic nerve
We hypothesized that early removal of senescent RGCs that secrete senescent associated secretory proteins (SASP) could protect remaining RGCs from senescence and death induced by intraocular pressure (IOP) elevation
We show that in transgenic animals expressing viral TK under the control of regulatory regions of p16Ink4a (Demaria et al, 2014), selective removal of early senescent cells in the retina is beneficial for neighboring cells undergoing cellular stress induced by IOP elevation

Summary

| INTRODUCTION

Glaucoma is comprised of progressive optic neuropathies characterized by degeneration of retinal ganglion cells (RGC) and resulting changes in the optic nerve It is a complex disease where multiple genetic and environmental factors interact (Skowronska-Krawczyk et al, 2015; Weinreb, Aung, & Medeiros, 2014). The analysis of p16KO mice suggested that lack of p16Ink4a gene protected RGCs from cell death caused by elevated IOP (Skowronska-Krawczyk et al, 2015). We hypothesized that early removal of senescent RGCs that secrete senescent associated secretory proteins (SASP) could protect remaining RGCs from senescence and death induced by IOP elevation To test this hypothesis, we used an established transgenic p16-3MR mouse model (Demaria et al, 2014) in which the systemic administration of the small molecule ganciclovir (GCV) selectively kills p16INK4a-expressing cells. We confirm the efficiency of the method by showing the reduced level of p16INK4a expression and lower number (a)

| MATERIALS AND METHODS

Findings

| DISCUSSION