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

Age-related macular degeneration is a major global cause of central visual impairment and seve re vision loss.With an aging population,the already immense economic burden of costly anti-vascular endothelial growth fa ctor treatment is likely to increase.In addition,current conventional treatment is only available for the late neovascular stage of age-related macular degeneration,and injections can come with potentially devastating complications,introducing the need for more economical and ris kfree treatment.In recent years,exosomes,which are nano-sized extracellular vesicles of an endocytic origin,have shown immense potential as diagnostic biomarkers and in the therapeutic application,as they are bestowed with characte ristics including an expansive cargo that closely resembles their parent cell and exceptional ability of intercellular communication and targeting neighboring cells.Exosomes are currently undergoing clinical trials for various conditions such as type 1 diabetes and autoimmune diseases;however,exosomes as a potential therapy for seve ral retinal diseases have just begun to undergo scrutinizing investigation with little literature on age-related macular degeneration specifically.This article will focus on the limited literature availa ble on exosome transplantation treatment in age-related macular degeneration animal models and in vitro cell cultures,as well as briefly identify future research directions.Current literature on exosome therapy using agerelated macular degeneration rodent models includes laser retinal injury,N-methyl-N-nitrosourea,and royal college of surgeon models,which mimic inflammatory and degenerative aspects of agerelated macular degeneration.These have shown promising results in preserving retinal function and morphology,as well as protecting photoreceptors from apoptosis.Exosomes from their respective cellular origins may also act by regulating the expression of various inflammatory cyto kines,mRNAs,and proteins involved in photo receptor degeneration pathways to exert a therapeutic effect.Various findings have also opened exciting prospects for the involvement of cargo components in remedial effects on the damaged macula or retina.

Retinal ganglion cell neuroprotection by growth factors and exosomes:lessons from mesenchymal stem cells

Retinal ganglions cells （RGCs） are responsible for propagating electrochemical information from the eye to the brain along their axons which make up the optic nerve. The loss of RGCs is characteristic in several conditions such as glaucoma and trau- matic optic neuropathy and leads to visual loss and blindness. While no therapy exists to directly treat RGCs, the use of bone marrow-derived mesenchymal stem cells （BMSCs） has shown promise in eliciting significant RGC neuroprotection.

Dental pulp stem cells, a paracrine-mediated therapy for the retina

Author contributions： Mead B was responsible for study conception and design, collection and^or assembly of data, data analysis and interpretation and manuscript writing. Logan A participated in study conception and design, data analysis and interpretation and manuscript writing. Berry M was responsible for manuscript writing. Scheven BA was in charge of study conception and design, data analysis and interpretation and manuscript writing. Leadbeater W participated in study conception and design, data analysis and interpretation and manuscript writing. All authors approved the final version of this paper.

Mesenchymal stem cell therapy for retinal ganglion cell neuroprotection and axon regeneration

Retinal ganglion cells （RGCs） are responsible for propagat- ing signals derived from visual stimuli in the eye to the brain, along their axons within the optic nerve to the superior colliculus, lateral geniculate nucleus and visu- al cortex of the brain. Damage to the optic nerve either through trauma, such as head injury, or degenerative dis- ease, such as glaucoma causes irreversible loss of function through degeneration of non-regenerating RGC axons and death of irreplaceable RGCs, ultimately leading to blindness （Berry et al., 2008）. The degeneration of RGCs and their axons is due to the loss of the necessary source of retrogradely transported neurotrophic factors （NTFs） being hindered by axonal injury. NTFs are survival factors for neurons and play a pivotal part in axon regeneration. Stem cells particularly mesenchymal stem cells （MSCs） have been shown to possess a natural intrinsic capacity for paracrine support, releasing multiple signalling mol- ecules including NTFs. By transplanting MSCs into the vitreous, they are positioned adjacent to the injured reti- na to provide paracrine-mediated therapy for the retinal neuronal cells （Johnson et al., 2010a; Mead et al., 2013）. Additionally, MSCs may be pre-differentiated into sup- portive glial-like cells, such as Schwann cells, which could further increase their potential for paracrine support of injured neurons （Martens et al., 2013）. Thus, MSCs have received considerable attention as a new cellular therapy for both traumatic and degenerative eye disease, acting as an alternative source of NTFs, protecting injured RGCs and promoting regeneration of their axons （Figure 1）.

The role of miRNA in retinal ganglion cell health and disease

miRNA are short non-coding RNA responsible for the knockdown of proteins through their targeting and silencing of complimentary m RNA sequences.The mi RNA landscape of a cell thus affects the levels of its proteins and has significant consequences to its health.Deviations in this mi RNA landscape have been implicated in a variety of neurodegenerative diseases and have also garnered interest as targets for treatment.Retinal ganglion cells are the sole projection neuron of the retina with their axons making up the optic nerve.They are a focus of study not only for their importance in vision and the myriad of blinding diseases characterized by their dysfunction and loss,but also as a model of other central nervous system diseases such as spinal cord injury and traumatic brain injury.This review summarizes current knowledge on the role of mi RNA in retinal ganglion cell function,highlighting how perturbations can result in disease,and how modulating their abundance may provide a novel avenue of therapeutic research.