Target specification and therapeutic potential of extracellular vesicles for regulating corneal angiogenesis, lymphangiogenesis, and nerve repair

Abstract

Extracellular vesicles, including exosomes, are small extracellular vesicles that range in size from 30 nm to 10 μm in diameter and have specific membrane markers. They are naturally secreted and are present in various bodily fluids, including blood, urine, and saliva, and through the variety of their internal cargo, they contribute to both normal physiological and pathological processes. These processes include immune modulation, neuronal synapse formation, cell differentiation, cancer metastasis, angiogenesis, lymphangiogenesis, progression of infectious disease, and neurodegenerative disorders like Alzheimer's and Parkinson's disease. In recent years, interest has grown in the use of exosomes as a potential drug delivery system for various diseases and injuries. Importantly, exosomes originating from a patient's own cells exhibit minimal immunogenicity and possess remarkable stability along with inherent and adjustable targeting capabilities. This review explores the roles of exosomes in angiogenesis, lymphangiogenesis, and nerve repair with a specific emphasis on these processes within the cornea. Furthermore, it examines exosomes derived from specific cell types, discusses the advantages of exosome-based therapies in modulating these processes, and presents some of the most established methods for exosome isolation. Exosome-based treatments are emerging as potential minimally invasive and non-immunogenic therapies that modulate corneal angiogenesis and lymphangiogenesis, as well as enhance and accelerate endogenous corneal nerve repair.

Fig. 1.

Exosomes communicate with their target cells via direct ligand–receptor interactions or by membrane fusion and intracellular cargo delivery. Upon reaching a target cell, membrane receptors within the exosome surface and plasma membrane of the target cell can interact, inducing a downstream signaling cascade in the recipient cell (A). The exosomal membrane can also fuse with the target cell’s plasma membrane, releasing the exosomal contents directly into the cytosol (B) [7]. Adapted with permission.

Fig. 2.

Protein–protein interactome network of 15 selected bioactive molecules, including growth factors and cytokines found in exosomes, and potential relationships among them related to corneal angiogenesis, lymphangiogenesis, and nerve regeneration. The levels of direct and indirect interaction of the exosomal components dictate their role as master regulators or single effectors in these processes. A higher number of interactions indicates a more prominent role. Data were generated using STRING analysis (https://string-db.org).

Fig. 3.

Receptor–ligand specificity can determine the type of physiologic response that occurs in many tissues upon exposure to exosomes. At least three different effects are observed in the cornea when exosomal cargo containing ligands triggers different downstream signals. If the exosome contains ligands that bind receptors associated with vascular endothelial cells (left figure), neovascularization is visible from the limbus into the central cornea. If the exosome ligands associate with receptors involved in LECs, lymphatic vessels will form from the periphery to the central cornea (middle figure). A third scenario is possible if the exosome ligands interact with receptors involved in nerve regeneration; then increased nerve density is observed through the entire cornea (right figure). Some ligands can interact with both blood vessels as well as nerves (i.e., VEGFA). However, the mechanisms that dictate the end result are still to be discovered. Adapted with permission [7,143-145].

Fig. 4.

Protein–protein interaction network for putative receptors specific to vascular endothelial cells, LECs, and neurons and their potential ligands generated using STRING analysis.