Enhancing Stem Cell Restoration of IOP Homeostasis by Senolytic Treatments

Oregon Health & Science University, Portland OR

Investigators

Abstract

Summary Glaucoma, a major blinding optic neuropathy, is a progressive, debilitating disease with visual field loss. The primary risk factor for the disease, as well as the one and only treatable parameter to delay bilateral blindness and slow the disease is to reduce the elevated intraocular pressure (IOP). The IOP is controlled and adjusted by the resistance to aqueous humor outflow. This resistance resides within the deepest portion of the trabecular meshwork (TM), called juxtacanalicular (JCT) region, and in the greater basement membrane of the inner wall cells of Schlemm's canal endothelium (SCE). IOP changes are sensed by JCT cells as mechanical stretching, and they react by modifying the outflow resistance to restore the IOP to normal. This is the IOP homeostatic response. However, this IOP homeostatic response is lost in glaucomatous eyes. In glaucoma there is also significant TM cell loss. We developed a model for human anterior segment TM cell loss, and in this model, IOP homeostasis is compromised. Transplanting TM cells, differentiated induced pluripotent stem cells, or human mesenchymal stem cells in this ex vivo model restores IOP homeostatic regulation. TM cells become senescent with increased passage in culture or with exposure to H2O2. Aged glaucomatous TM cells exhibit much higher levels of senescence than normal aged TM cells in tissue. Presumably, these senescent cells are occupying space in the TM but are not facilitating the IOP homeostatic response or may even be diminishing it. Transplantation of stem cells into the TM where many senescent cells are present may diminish how many stem cells can attach and integrate to restore IOP homeostatic function. Senotherapeutics are recently developed drugs which act upon the senescent cells. Senolytic pharmaceuticals can selectively clear senescent cells removing them from occupying tissue space or can reverse some of the negative changes that are characteristic of senescent cells. Senoreverters can reverse the properties of senescent cells and restore some or complete function. This might include restoration of lost IOP homeostatic capability. Herein, we propose to use senolytics and separately senoreverters to restore TM cell IOP homeostatic function to glaucomatous tissue with or without the assistance of stem cell transplantation. This has the potential to lead to new innovative therapies to restore glaucomatous IOP homeostatic capability.