Roles of exosomes in the normal and diseased eye

doi:10.1016/j.preteyeres.2017.04.004

Progress in Retinal and Eye Research

Volume 59, July 2017, Pages 158-177

https://doi.org/10.1016/j.preteyeres.2017.04.004 Get rights and content

Abstract

Exosomes are nanometer-sized vesicles that are released by cells in a controlled fashion and mediate a plethora of extra- and intercellular activities. Some key functions of exosomes include cell-cell communication, immune modulation, extracellular matrix turnover, stem cell division/differentiation, neovascularization and cellular waste removal. While much is known about their role in cancer, exosome function in the many specialized tissues of the eye is just beginning to undergo rigorous study. Here we review current knowledge of exosome function in the visual system in the context of larger bodies of data from other fields, in both health and disease. Additionally, we discuss recent advances in the exosome field including use of exosomes as a therapeutic vehicle, exosomes as a source of biomarkers for disease, plus current standards for isolation and validation of exosome populations. Finally, we use this foundational information about exosomes in the eye as a platform to identify areas of opportunity for future research studies.

Section snippets

Exosomes: a brief overview

The endocytic pathway consists of compartments involved in the internalization of extracellular ligands or cellular components, recycling of those components to the plasma membrane, and/or their degradation (Gould and Lippincott-Schwartz, 2009, Klumperman and Raposo, 2014). During the maturation process of early endosomes into late endosomes (Stoorvogel et al., 1991), intraluminal vesicle (ILVs) accumulate. Because of their appearance, these late endosomes are generally referred to as

Methods for exosome isolation – pros and cons

A number of methods can be used for isolating exosomes and small EVs. However, the EV preparations resulting from the different methods span a wide range of purities and properties. Thus, it is very important to choose the isolation method that is appropriate for the downstream analysis methods that will be used or the experiments that will be done with the isolated EVs. In particular, complex biological fluids such as plasma, serum and urine pose difficulties for EV isolation.

Following is a

Exosomes and their role in immune regulation

Much of the early seminal work describing, defining and characterizing exosomes was done with exosomes released from immune cells (Blanchard et al., 2002, Escola et al., 1998, Raposo et al., 1996, Skokos et al., 2001, Thery et al., 2006). Over the past decade, the role of exosomes in the regulation and maintenance of immune function has become an area of intense research, displaying substantial promise for novel diagnostic and therapeutic approaches (Robbins and Morelli, 2014). We focus on two

Invadosomes in the trabecular meshwork (TM) and lamina cribrosa (LC)

Exosomes have recently been shown to facilitate interactions between the cell and ECM by acting as key components of cellular structures called invadosomes (Hoshino et al., 2013, Mu et al., 2013). This term encompasses specialized cell structures that range from podosomes to invadosomes where focal turnover of ECM takes place (Saltel et al., 2011). A specialized subpopulation of exosomes is likely released into the pericellular space at or near invadosomes where active ECM remodeling is taking

Angiogenesis in cancer

The involvement of exosomes and small EVs in angiogenesis in cancer has been the focus of intense research in the last couple of years (Kalluri, 2016, Whiteside, 2016b). Exosomes and small EVs have been shown to modulate angiogenesis in tumors by both pro- and anti-angiogenic pathways (Ribeiro et al., 2013). For example, exosome release is increased by hypoxia that often occurs in tumors, and these exosomes stimulate angiogenesis, when taken up by endothelial cells (Hong et al., 2009, Park

Stem cells and exosomes

Cell death of largely post-mitotic cells is part of the disease process in all eye diseases; therefore stem cell-based approaches aimed at cell replacement are being actively studied for therapy and/or intervention. For example, patients with ocular hypertension and glaucoma have fewer TM cells (Alvarado et al., 1984, Gottanka et al., 2006, Rodrigues et al., 1976) and vision loss in glaucoma is due to death of retinal ganglion cells (Quigley, 1993). Patients with a late dry form of AMD known as

Exosome biomarkers for eye diseases

Interest in utilizing exosomes and other EVs to identify biomarkers of disease has increased exponentially in recent years (Gonzalez and Falcon-Perez, 2015). It is easy to understand why the perceived potential for development of exosome-based diagnostic assays is so large. Exosomes and EVs have several unique features that make them ideal as targets for finding new biomarkers: (i) the lipid bilayer provides protection for RNA, DNA, and proteins inside the exosome from nucleases and proteases

Exosomes as therapeutic agents

Today the two leading causes of irreversible blindness in Western societies are AMD and glaucoma. By 2020 it is estimated that 196 million people worldwide will have AMD (Wong et al., 2014) and 79.6 million people worldwide will have glaucoma (Quigley and Broman, 2006). The goal of current therapeutic approaches to treat these late onset diseases is not to reverse the disease course, but only to halt further progression of tissue damage and vision loss. Additionally, many of the therapeutic

Conclusions and future directions

The etiology of a number of eye diseases involve activation of immune cells, inflammation, degeneration of neurons, neovascularization and fibrosis (Cousins et al., 2004, Hernandez et al., 1990, Howell et al., 2013, Ishikawa et al., 2016, Neely and Gardner, 1998, Pflugfelder, 2004, Tektas and Lutjen-Drecoll, 2009, Vranka et al., 2015). As discussed in this review, exosomes are likely mediating some, if not all of these effects. More importantly, the use of exosomes has been experimentally shown

Acknowledgments

The authors thank Dr. Nikolai Skiba for mass spectrometric analyses. This study was supported by NIH EY023468 (WMD), EY 026161 (CBR), EY023287 (WDS), EY022359 (WDS), EY019696 (WDS), P30 EY005722 (Core grant), the BrightFocus Foundation M2015221 (MK), a Glaucoma Research Foundation Shaffer Grant (WMD, WDS), and the Foundation Fighting Blindness (CBR). In addition, Duke University Department of Ophthalmology is supported by an unrestricted grant to the Duke Eye Center from Research to Prevent

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Roles of exosomes in the normal and diseased eye

Abstract

Section snippets

Exosomes: a brief overview

Methods for exosome isolation – pros and cons

Exosomes and their role in immune regulation

Invadosomes in the trabecular meshwork (TM) and lamina cribrosa (LC)

Angiogenesis in cancer

Stem cells and exosomes

Exosome biomarkers for eye diseases

Exosomes as therapeutic agents

Conclusions and future directions

Acknowledgments

Anal. Biochem.

Prog. Brain Res.

Transl. Res.

Ophthalmology

Prog. Retin. eye Res.

Exp. Cell Res.

Prog. Retin Eye Res.

Trends Neurosci.

Trends Cell Biol.

Blood

Exp. Eye Res.

Exp. Eye Res.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Eye Res.

J. Biol. Chem.

J. Biol. Chem.

Dev. Biol.

Am. J. Ophthalmol.

Cell Rep.

Exp. Neurol.

Blood

Molecular underpinnings of corneal angiogenesis: advances over the past decade

Int. J. Ophthalmol.

Human retinal pigment epithelium cells as functional models for the RPE in vivo

Invest Ophthalmol. Vis. Sci.

Induced pluripotent stem cells restore function in a human cell loss model of open-angle glaucoma

Stem Cells

Concentration of Epstein-Barr virus from cell culture fluids with polyethylene glycol

J. Gen. Virol.

Specialized podosome- or invadopodia-like structures (PILS) for focal trabecular meshwork extracellular matrix turnover

Invest Ophthalmol. Vis. Sci.

The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration

Am. J. Ophthalmol.

Concise review: limbal stem cell deficiency, dysfunction, and distress

Stem Cells Transl. Med.

Monocyte modulation of aqueous outflow and recruitment to the trabecular meshwork following selective laser trabeculoplasty

Arch. Ophthalmol.

Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes

Nat. Biotechnol.

Proteomic characterization of the human centrosome by protein correlation profiling

Nature

Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles

J. Exp. Med.

Methods for microvesicle isolation and selective removal

Syst. Biosci.

Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion

Proc. Natl. Acad. Sci. U. S. A.

Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells

J. Cell Mol. Med.

Syndecan-syntenin-ALIX regulates the biogenesis of exosomes

Nat. Cell Biol.

Heparin affinity purification of extracellular vesicles

Sci. Rep.

The use of cell lines to “model” ocular tissues: cautionary tales

Invest Ophthalmol. Vis. Sci.

TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex

J. Immunol.

Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells

Front. Immunol.

Ophthalmologic stem cell transplantation therapies

Regen. Med.

Age and disease-related structural changes in the retinal pigment epithelium

Clin. Ophthalmol.