Mesenchymal stem cell therapies for the trabecular meshwork in glaucoma
Snider, Eric Joseph
MetadataShow full item record
Glaucoma, a leading cause of blindness, affects over 70 million people worldwide, and its incidence is expected to continue to rise with an aging population. The exact origin for primary open angle glaucoma (POAG), the most prevalent form of glaucoma, is unknown, but an increased intraocular pressure (IOP) is a well-established risk factor for POAG. IOP is largely determined by aqueous humor production rate and outflow through drainage tissues in the anterior eye, specifically through the trabecular meshwork. In POAG, the cellularity of the trabecular meshwork (TM) is significantly decreased in comparison to healthy eyes, which presumably leads to loss of TM function, higher outflow resistance and, thus, increased IOP. As a result, therapies striving to restore TM cellularity could alter glaucoma progression. This research will investigate the use of mesenchymal stem cells (MSCs) to restore trabecular meshwork function. MSC therapies represent a new, largely unstudied, therapeutic approach for the TM, and, as such, methods and procedures for assessing differentiation, delivering cells to the eye, and assessing these cells’ therapeutic potential for POAG are not yet established. The overall objective of this thesis was to develop solutions to these essential first steps so that MSC therapies can be properly assessed and implemented. We first established methods to characterize differences between MSCs and TM cells at the RNA, protein, and functional levels for assaying MSC differentiation. For studying delivery of MSCs to the eye, we implemented an ultrasound and photoacoustic imaging platform for tracking MSC delivery to the TM in real time. Next, magnetic nanoparticles were used to label and steer MSC to the TM at high efficiency and uniformity compared to passive delivery approaches. Lastly, an improved ex vivo model of POAG was developed to properly mimic glaucomatous changes in the TM triggered by oxidative stress-induced damage. Overall, this thesis established methods and procedures needed for developing MSC therapies for POAG. Our results allow MSC differentiation to be properly characterized, MSC location to be monitored in real-time in the eye, MSC delivery to be improved with magnetic nanoparticles, and MSC therapeutic benefit to be assessed using a suitable ex vivo model. Future work should assess the potential of MSCs for refunctionalizing the TM as a novel POAG therapy.