Potential Use Of Mesenchymal Stem Cells In The Treatment Of Glaucoma

Updated: Feb 2

Glaucoma is a group of eye conditions that damage the optic nerve, the health of which is vital for good vision. According to the American Academy of Ophthalmology, with all types of glaucoma, the nerve connecting the eye to the brain is damaged, usually due to high eye pressure. The most common type of glaucoma (open-angle glaucoma) often has no symptoms other than slow vision loss. Angle-closure glaucoma, although rare, is a medical emergency and its symptoms include eye pain with nausea and sudden visual disturbance. Treatment includes medications and various surgical options. Clinically, glaucoma is defined as a condition with characteristic appearance of optic disc (optic disc cupping) and corresponding visual field loss.


A critical component in the eye, critical for maintaining appropriate intraocular pressure (IOP) in the eye, is the trabecular meshwork (TM), an area of tissue in the eye located around the base of the cornea. The tissue is populated by specialized cells that are crucial for its function. The number of these TM cells declines with age and is particularly low in individuals with primary open-angle glaucoma (POAG), a disease that is frequently associated with meshwork dysfunction and elevated IOP. As an example, in pigmentary glaucoma (a subset of POAG), pigment can rub off the back of the iris. Pigment is what gives your eyes color. This pigment then floats around to other parts of the eye. The tiny bits of pigment can clog your eye's TM. This can lead to high IOP. In addition to poor drainage, excessive aqueous humor production, direct trauma to the eye, certain medications, etc. all can lead to elevated IOP.




Furthermore, the Retinal Nerve Fiber Layer (RNFL) which is composed of retinal ganglion cell (RGC) axons, progressively degenerates in glaucoma, resulting in thinning and disappearance of axon bundles from the RNFL. Jammal, et al., in a retrospective study of over 14,000 patients, suggested that for those patients with elevated IOP, there was a correlation between the increase IOP and deterioration of the RNFL.


As previously stated, treatment options are limited to medications such as beta blockers, prostaglandins, alpha-adrenergic agonist, carbonic anhydrase inhibitors, rho kinase inhibitors and miotic or cholinergic agents. Surgical options include trabeculectomy which may include removal of part of the trabecular network and possible insertion of a shunt and laser trabeculoplasty. There are also less invasive options as well.


However, more recently, it has been hypothesized by Astero-Castro, et al. that molecular changes at the whole cell, gene expression, and electrophysiological level of the neurons can contribute to the degeneration of the RGC. This suggests that glaucoma, while currently viewed to involve the neuronal environment and external effects as a source of causative factors, may be viewed as a neurodegenerative disorder. To test their hypothesis, they described human induced pluripotent stem cells (hiPSCs) as a reliable cellular tool to model neurodegenerative aspects of glaucoma to reveal the multiple pathological molecular mechanisms underlying disease development. They concluded glaucoma represents a neurodegenerative disease caused by intrinsic vulnerability factors. The characteristic pathology of RGC degeneration in different types of glaucoma associates with different risk factors, suggesting a vulnerability of these cells to disease independent of IOP. This suggests that regenerative medicine techniques, particularly those involving stem cells should be investigated.


For example, Manuguerra-GagnÉ, et al. used a laser-induced model of open angle glaucoma (OAG) to evaluate the potential of bone marrow cell populations and the mechanisms involved in tissue repair. They investigated laser-induced tissue remodeling as a method of targeting effector cells into damaged tissues and demonstrated that among bone marrow cells, mesenchymal stem cells (MSC) induce trabecular meshwork regeneration based on modified version of the laser-induced animal (rat) model developed by Levkovitch-Verbin et al. which allowed for an internal control consisting of an untreated segment within the laser-treated eye. MSC injection into the ocular anterior chamber lead to far more efficient decrease in intraocular pressure (IOP) (p < .001) and healing than hematopoietic cells.


Cui et al. obtained similar results using bone marrow MSC (BMSC) in rat models. Their study found that BMSC transplantation is protective in aged rats with retinal ganglion cell loss induced by glaucoma. Increased retinal ganglion cell survival was positively correlated with preservation of visual acuity 10 weeks after induction of glaucoma. However, they did note that there was more several RGC loss in aged rats versus young rats suggesting that neuroprotective treatment as early as possible is critical to preserve more retinal ganglion cells.


While the foregoing provides but two examples of the therapeutic potential of using MSC to address retinal damage and concurrent loss of vision, there are numerous other studies employing animal models that suggest that MSC, and as well MSC derived exosomes, are promising therapeutic approaches to mitigate glaucoma and other neuro-visual disorders.


Written by Lawrence D. Jones, PhD, Science Writer


Keywords: Glaucoma, Mesenchymal Stem Cells, Retinal Ganglion


References:

1. Kwon, S., Kim, S. H., Khang, D., & Lee, J. Y. (2020).Potential Therapeutic Usage of Nanomedicine for Glaucoma Treatment, International Journal of Nanomedicine, Volume 15, 5745–5765. doi:10.2147/ijn.s254792

2. Kierstan Boyd (2020), What is Glaucoma, American Academy of Ophthalmology, https://www.aao.org/eye-health/diseases/what-is-glaucoma

3. Jammal, A. A., Thompson, A. C., Mariottoni, E. B., Estrela, T., Shigueoka, L. S., Berchuck, S. I., & Medeiros, F. A. (2020). Real-World Impact of Intraocular Pressure Control on Rates of Retinal Nerve Fiber Layer Loss in a Large Clinical Population. Ophthalmology. doi:10.1016/j.ophtha.2020.06.027

4. Artero-Castro, A., Rodriguez-Jimenez, F. J., Jendelova, P., VanderWall, K. B., Meyer, J. S., & Erceg, S. (2020). Glaucoma as a Neurodegenerative Disease Caused by Intrinsic Vulnerability Factors. Progress in Neurobiology, 101817. doi:10.1016/j.pneurobio.2020.101817

5. Manuguerra-GagnÉ, R., Boulos, P. R., Ammar, A., Leblond, F. A., Krosl, G., Pichette, V., … Roy, D.-C. (2013). Transplantation of Mesenchymal Stem Cells Promotes Tissue Regeneration in a Glaucoma Model Through Laser-Induced Paracrine Factor Secretion and Progenitor Cell Recruitment. STEM CELLS, 31(6), 1136–1148. doi:10.1002/stem.1364

6. Cui, H., Hu, Y., Wang, Z. M., Tan, H. B., Rong, H., & Cui, H. P. (2013). Bone marrow mesenchymal stem cells protect against retinal ganglion cell loss in aged rats with glaucoma. Clinical Interventions in Aging, 1467. doi:10.2147/cia.s47350

7. Nuzzi R, Caselgrandi P, Vercelli A, Cantore S. Effect of Mesenchymal Stem Cell-Derived Exosomes on Retinal Injury: A Review of Current Findings. Stem Cells International. 2020;2020:1-9.

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