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Markus H Kuehn, Wei Zhu, Oliver W Gramlich, Lauren Laboissonniere, Jeffrey Trimarchi, Budd A Tucker; Restoration of trabecular meshwork cellularity and function following iPSC transplantation in vivo. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Primary open angle glaucoma is frequently associated with loss and dysfunction of trabecular meshwork (TM) cells. The purpose of this study was to determine if restoration of TM cellularity, using TM cells derived from induced pluripotent stem cells (iPSC), can lead to lasting functional rescue of the TM in a genetic mouse model of the disease.
Mouse iPSC were differentiated into TM-like cells (iPSC-TM) and injected into the anterior chamber of MYOCY437H mice (N=22) as described previously. Controls included MYOCY437H mice receiving sham injections (N=16) or fibroblasts (N=8) as well as age matched wild type mice (N=20). Intraocular pressure (IOP) was measured by rebound tonometry and aqueous humor outflow facility by direct cannulation. 12 weeks after transplantation retinal ganglion cell (RGC) and TM cellularity was assessed by immunohistochemistry and gene expression patterns in the TM was determined using gene expression arrays.
When compared to sham injected MYOCY437H mice, animals having received iPSC-TM display significantly lower IOP (16.4±3.1 vs 12.2±2.8 mmHg, P=0.0006) and higher aqueous humor outflow facility (0.016±0.005 vs. 0.027±0.01 µl/min/mmHg, P=0.04). Treated mice also display higher RGC density (2222.1±250.4 vs. 1706.9±491.3 RGC/mm2) and higher TM cellularity than control mice (25.7±7.3 vs. 54.9±7.2 TM/section, P=6.83E-06). However, surviving iPSC-TM are rarely observed in the TM 12 weeks after transplantation. These values observed in iPSC-TM recipients MYOCY437H mice resemble those of wild type mice. In contrast, sham injected eyes or those having received a transplantation of unrelated cells, do not differ significantly from those of age mated untreated MYOCY437H animals. Gene expression analyses demonstrate that a large number of cell cycle associated genes were expressed at higher levels in the TM of eyes having received transplanted iPSC-TM.
These data demonstrate that functional restoration of glaucomatous TM, resulting decreased IOP and RGC rescue, is possible using iPSC-TM. Unexpectedly, the effect of iPSC-TM transplantation does not appear to be a functional replacement of lost TM cells. Rather it appears that transplantation induces a proliferative response of the remaining endogenous TM cells that results in normal TM cellularity and restoration of IOP control.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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