Restoration of Aqueous Humor Outflow Following Transplantation of iPSC-Derived Trabecular Meshwork Cells in a Transgenic Mouse Model of Glaucoma

Abstract

PurposePrimary open-angle glaucoma (POAG) is particularly common in older individuals and associated with pathologic degeneration of the trabecular meshwork (TM). We have shown previously that transplantation of induced pluripotent stem cell (iPSC) derived TM cells restores aqueous humor dynamics in young transgenic mice expressing a pathogenic form of human myocilin (Tg-MYOCY437H). This study was designed to determine if this approach is feasible in older mice with more pronounced TM dysfunction.MethodsMouse iPSC were differentiated toward a TM cell phenotype (iPSC-TM) and injected into the anterior chamber of 6-month-old Tg-MYOCY437H or control mice. IOP and aqueous humor outflow facility were recorded for up to 3 months. Transmission electron microscopy, Western blot, and immunohistochemistry were performed to analyze TM morphology, quantify endoplasmic reticulum (ER) stress, and assess TM cellularity.ResultsA 12 weeks after transplantation, IOP in iPSC-TM recipients was statistically lower and outflow facility was significantly improved compared to untreated controls. The number of endogenous TM cells increased significantly in iPSC-TM recipients along with the appearance of TM cells immmunopositive for a marker of cellular division. Morphologically, transplantation of iPSC-TM preserves ER structure 12 weeks after transplantation. However, myocilin and calnexin expression levels remain elevated in transplanted eyes of these 9-month-old Tg-MYOCY437H mice, indicating that ER stress persists within the TM.ConclusionsTransplantation of iPSC-TM can restore IOP and outflow facility in aged Tg-MYOCY437H mice. This type of stem cell–based therapy is a promising possibility for restoration of IOP control in some glaucoma patients.

Adipose‐derived stem cells integrate into trabecular meshwork with glaucoma treatment potential

“…After bone marrow‐derived MSCs were injected into laser‐treated rat anterior chambers, IOP rapidly declined to normal levels and TM structure was restored at one month 36 . iPSCs can be induced to differentiate into TM cells in vitro, 37 and can restore TM function ex vivo 38 and in vivo 39,40 . Thus, both MSCs and iPSCs are potential candidates as cell therapy resources.…”

Tunneling Nanotubes and the Eye: Intercellular Communication and Implications for Ocular Health and Disease

“…Mesenchymal stem cell (MSC) transplantation has shown to be neuroprotective for RGCs [122], and MSCs offer an attractive therapeutic option for repopulating the cells of the TM of POAG patients, which have a marked reduction in the TM cell number [123]. Several groups have shown that introduction of MSCs [124], or induced pluripotent stem cells (iPSCs) [125][126][127], may restore TM IOP regulation function. In both anterior and posterior glaucoma stem cell therapies, it is conceivable that TNTs formed between stem cells and resident cells could promote survival of the remaining endogenous host cells.…”

Trabecular meshwork cells are a valuable resource for cellular therapy of glaucoma

“…83,84 Zhu et al reported that aqueous humour out-flow was restored following transplantation of iPSC-derived TM cells in a transgenic mouse model of glaucoma. 84 Their results suggest that transplantation of iPSC-TM may restore out-flow facility and IOP in aged mice. However, this model is not perfect because the expression of myocilin and calnexin is still elevated in transplanted eyes of the mice, suggesting that ER stress is not corrected in the TM.…”