RPE-derived exosomes rescue the photoreceptors during retina degeneration: an intraocular approach to deliver exosomes into the subretinal space

Abstract

Retinal degeneration (RD) refers to a group of blinding retinopathies leading to the progressive photoreceptor demise and vision loss. Treatments against this debilitating disease are urgently needed. Intraocular delivery of exosomes represents an innovative therapeutic strategy against RD. In this study, we aimed to determine whether the subretinal delivery of RPE-derived exosomes (RPE-Exos) can prevent the photoreceptor death in RD. RD was induced in C57BL6 mice by MNU administration. These MNU administered mice received a single subretinal injection of RPE-Exos. Two weeks later, the RPE-Exos induced effects were evaluated via functional, morphological, and behavior examinations. Subretinal delivery of RPE-Exos efficiently ameliorates the visual function impairments, and alleviated the structural damages in the retina of MNU administered mice. Moreover, RPE-Exos exert beneficial effects on the electrical response of the inner retinal circuits. Treatment with RPE-Exos suppressed the expression levels of inflammatory factors, and mitigated the oxidative damage, indicating that subretinal delivery of RPE-Exos constructed a cytoprotective microenvironment in the retina of MNU administered mice. Our data suggest that RPE-Exos have therapeutic effects against the visual impairments and photoreceptor death. These findings will enrich our knowledge of RPE-Exos, and highlight the discovery of a promising medication for RD.

Extracellular vesicles as a potential therapeutic for age-related macular degeneration

“…Interestingly, Chen et al (2021b) found that hRPC-exos had better efficacy in preventing temporal ONL thinning compared to nasal. hRPC-exos also induced downregulation of BAX and Caspase 3 but increased BCL-2, which is consistent with results from Wang et al on ARPE-exos (Wang et al, 2021). A finding unique to this article was that an in vitro co-culture showed hRPC-exos co-localized with human microglial cell line HMC3 and significantly reduced protein and gene levels of inflammatory proteins, which may be yet another mechanism of exosomes.…”

“…Both papers found that exosome treatment significantly preserved ONL thickness and scotopic ERG amplitudes of alpha and beta waves, retained normal retinal architecture and protected cone photoreceptors as shown in immunohistochemical staining (Wang et al, 2021) and TUNEL analysis (Deng et al, 2021). Furthermore, Wang et al (2021) also showed copious punctate and opsin staining in the retina which indicated cone photoreceptors were undamaged, with M & S cones best protected against MNU-induced injury, whereas no staining was found in the untreated MNU control group. Visual acuity, contrast sensitivity, and optokinetic behaviors tests displayed all-round protection of visual functions from ARPE-exo treatment which was not previously shown.…”

“…Using the MNU model, exosomes derived from human adult retinal pigment epithelial cell line 19 (ARPE-exos) (Wang et al, 2021), as well as exosomes derived from mouse bone marrow (BMSC-exos) (Deng et al, 2021) demonstrated common findings with Yu et al (2016). Both papers found that exosome treatment significantly preserved ONL thickness and scotopic ERG amplitudes of alpha and beta waves, retained normal retinal architecture and protected cone photoreceptors as shown in immunohistochemical staining (Wang et al, 2021) and TUNEL analysis (Deng et al, 2021). Furthermore, Wang et al (2021) also showed copious punctate and opsin staining in the retina which indicated cone photoreceptors were undamaged, with M & S cones best protected against MNU-induced injury, whereas no staining was found in the untreated MNU control group.…”

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

“…RPE-derived exosomes (RPE-Exos) have also shown promising results in the treatment of RP. Recently, in C57BL6 mice with N-methyl-N-nitrosourea (MNU)-induced retinal detachment, it was shown that RPE-Exo treatment restores visual function by rescuing photoreceptor cells, significantly lowering TNFα and ILβ mRNA expression and inhibiting apoptosis pathway activation [ 231 ]. Similarly, MSC-Exos administration was shown to inhibit apoptosis induced by MNU and block retinal degeneration through the upregulation of miR-21 involved in key regulatory pathways [ 232 , 233 ].…”

Calpain-2 Facilitates Autophagic/Lysosomal Defects and Apoptosis in ARPE-19 Cells and Rats Induced by Exosomes from RPE Cells under NaIO3 Stimulation

“…RPE cells can secrete exosomes in a paracrine manner to interfere with neighboring cells. Furthermore, the pathological process of eye diseases could be influenced by exosomes delivered via intranasal, intraocular, intravenous, and other mechanisms [ 4 ]. The role of RPE-derived exosomes in a potentially harmful oxidative response has been well established under photooxidative blue-light stimulation conditions [ 5 ].…”