Retinal ganglion cells (RGC) are the sole projection neuron of the retina and their axons make up the optic nerve. Damage to the optic nerve can come in many forms including neurodegenerative diseases like glaucoma, (affecting >7M EU citizens and increasing each year), as well as traumatic neuropathy. Traumatic injury affecting the optic nerve similarly leads to the death of RGC and blindness with an estimated 1-5% of head injuries resulting in optic nerve damage. The functional deficit and lack of recovery is because RGC and their axons are part of the central nervous system (CNS) and thus suffer from two unfortunate characteristics, they are irreplaceable, and their axons are incapable of regeneration.
Current research and ongoing clinical trials suggests mesenchymal stem cells (MSC), such as those isolated from bone marrow, are an effective treatment for injured RGC, despite the mechanisms being poorly understood. MSC are a self-replicating multipotent stromal cell isolated from mesenchymal tissues. I and others have demonstrated the therapeutic efficacy of MSC in models of traumatic neuropathy and glaucoma, in vitro and in vivo. In retinal cultures, MSC proved neuroprotective and neuritogenic for injured RGC. After ONC, MSC transplanted into the vitreous were able to promote significant neuroprotection of RGC and regeneration of their axons. In animal models of glaucoma, MSC promote the survival of RGC and their axons and preserve their function.
Although the efficacy is well established, the mechanisms by which MSCs protect RGC and promote regeneration of their axons is poorly understood, although strongly believed to be paracrine-mediated (through the secretion of factors). Mounting evidence exists for the potential of MSC to benefit nearby injured tissues through the secretion of exosomes. Exosomes are endocytic-derived structures composed of proteins, lipids and mRNA surrounded by a phospholipid bi-layer that are secreted into the extracellular space. Exosomes contain (along with proteins) mRNA and miRNA, which are both functional and, when delivered to another cell via fusion with the cell membrane, lead to the translation of new proteins or miRNA-mediated knockdown of genes. Various studies have shown that the protective effect MSC provide is indeed exosome-mediated. Currently MSC exosomes remain untested in the eye and exosomes in general have not been tested as a treatment for injured RGC. Equally their mechanism of action as a whole is poorly understood with very few miRNA candidates identified as the active components.
The global aim of this project is to utilize exosomes from various sources and under different isolation techniques to promote survival of RGC and regeneration of their axons.
