Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Abstract

Glaucoma is a common cause of vision loss or blindness and reduction of intraocular pressure (IOP) has been proven beneficial in a large fraction of glaucoma patients. The IOP is maintained by the trabecular meshwork (TM) and the elevation of IOP in open-angle glaucoma is associated with dysfunction and loss of the postmitotic cells residing within this tissue. To determine if IOP control can be maintained by replacing lost TM cells, we transplanted TM-like cells derived from induced pluripotent stem cells into the anterior chamber of a transgenic mouse model of glaucoma. Transplantation led to significantly reduced IOP and improved aqueous humor outflow facility, which was sustained for at least 9 wk. The ability to maintain normal IOP engendered survival of retinal ganglion cells, whose loss is ultimately the cause for reduced vision in glaucoma. In vivo and in vitro analyses demonstrated higher TM cellularity in treated mice compared with littermate controls and indicated that this increase is primarily because of a proliferative response of endogenous TM cells. Thus, our study provides in vivo demonstration that regeneration of the glaucomatous TM is possible and points toward novel approaches in the treatment of this disease.G laucoma is one of the most common causes of irreversible vision loss and blindness worldwide; ∼60 million suffer from this disease, and of these, 7 million are blind (1). By definition all glaucoma involves some degree of vision loss, which is because of the death of retinal ganglion cells (RGC), as well as degeneration of the optic nerve head, the optic nerve, and the lateral geniculate nucleus (2, 3). Advanced age and elevated intraocular pressure (IOP) are the two most significant risk factors for the development of glaucoma. Elevated IOP is typically a result of disturbances in the balance of aqueous humor production and drainage. Aqueous humor is continuously synthesized within the eye and drained primarily through the trabecular meshwork (TM), a specialized structure located anterior to the root of the iris. Although occlusion of the aqueous humor outflow pathways can occur through several mechanisms, in the United States and other Western populations the most common form of glaucoma is primary open angle glaucoma (POAG), which manifests no gross abnormalities to the anterior portion of the eye.Randomized clinical trials have shown that reduction of IOP slows the onset and progression of glaucoma, even in patients without suspicious elevation of IOP (4, 5). Although there has been increasing awareness that factors other than elevated IOP contribute to glaucomatous damage, to date all treatments for glaucoma remain aimed at reducing IOP either through surgical or medical means, which has resulted in significant preservation of vision and increased quality of life for millions of glaucoma patients (6, 7).Although the TM in eyes with POAG appears relatively normal at a gross morphological level, a number of more subtle changes influencing the mechanical properties of the TM collage...

Roles of exosomes in the normal and diseased eye

“…A number of ocular surface diseases involve loss of cells on the surface and endothelium of the cornea (Ahmad, 2012). For all of these ocular diseases, researchers have proposed that stem cell-based therapy could be used to restore tissue health and function (Abu-Hassan et al, 2015; Al-Shamekh and Goldberg, 2014; Erbani et al, 2016; Mead et al, 2015; Nakamura et al, 2016; Roubeix et al, 2015; Zhu et al, 2016). One strategy for replacing lost cells is to transplant stem cells into the affected areas where they differentiate into the desired cell type and restore tissue/organ function (Blenkinsop et al, 2012).…”

“…Embryonic stem cell (ESC) derived precursors and induced pluripotent stem cells (iPSCs) have also been transplanted to replace degenerated photoreceptors and RPE cells (Gonzalez-Cordero et al, 2013; Meyer et al, 2009). In the trabecular meshwork, iPSCs have been used to repopulate the meshwork and/or provide trophic factors that induce proliferation in endogenous cells (Abu-Hassan et al, 2015; Zhu et al, 2016). …”

“…Finally, exosomes can induce proliferation in a number cell types (Deregibus et al, 2007; Jeong et al, 2014; Raimondo et al, 2015). Proliferation of TM cells can restore IOP homeostasis in animal models of glaucoma (Zhu et al, 2016). …”

Freeze-thaw decellularization of the trabecular meshwork in an ex vivo eye perfusion model

“…Recent studies suggested not only low TM cellularity (Alvarado, Murphy & Juster, 1984;Baleriola et al, 2008), but also TM cytoskeleton and phagocytosis changes in primary open angle glaucoma (Clark et al, 1995;Fatma et al, 2009;Izzotti et al, 2010;Saccà, Pulliero & Izzotti, 2015;Peters et al, 2015;Micera et al, 2016). Repopulating diseased TM with fresh, functional TM cells has been shown to restore homeostasis of normal outflow and thus might represent a novel therapeutic breakthrough (Du et al, 2013;Abu-Hassan et al, 2015;Yun et al, 2016;Zhu et al, 2016). …”

Two-Year Outcomes of Ab Interno Trabeculectomy with the Trabectome for Chinese Primary Open Angle Glaucoma: A Retrospective Multicenter Study

“…In glaucomatous eyes, diseased TM has a reduced facility and shows reduced phagocytosis [25,26], increased stiffness [27], and stress fiber formation [26]. Either removing TM surgically [28] or rehabilitating TM function by stem cells [29] can restore normal outflow and decrease IOP in previous studies. In the current study, our results showed that ab interno trabeculectomy with the Trabectome efficiently reduced IOP and the number of glaucoma medications with an overall success rate of 76% during a 2-year follow-up.…”