Magnetically-steered Human Mesenchymal Stem Cells Lower Intraocular Pressure (IOP) for 9 Months in Mice

Abstract

Purpose : Sustained IOP lowering via stem cell delivery to the trabecular meshwork (TM) would be useful in treating glaucoma. Here, we evaluate stem cell-induced IOP lowering in transgenic mice, using a highly efficient and specific magnetically-driven method for cell delivery to the TM [1].

Methods : Transgenic MYOC^Y437H mice (Tg; a model of myocilin glaucoma [2]; F1 SJLxBL6 background) received an intracameral injection (1.5 µl, 1000 cells/µl) of human adipose-derived mesenchymal stem cells (hADMSCs), induced pluripotent stem cells (iPSCs) differentiated to TM phenotype (iPSC-TM), or saline (sham control) at age 6-7 mo. Cells were labeled with superparamagnetic FeO₂ nanoparticles (SPIONs) and steered to the TM using a point magnet as described [1]. IOP was measured (Tonolab) at 1 (“short”), 3-4 (“mid”) or 9 (“long-term”) months after injection. Outflow facility was measured post mortem [3]. To determine TM cellularity, DAPI-stained nuclei were counted in the TM in sagittal cryosections and normalized by anterior-posterior TM length.

Results : Surprisingly, Tg animals did not develop ocular hypertension vs. wild-type (WT) controls. hADMSC delivery at short-term led to a 27% decrease in IOP vs. sham and remained similarly low at later time points (Fig 1; p values on figure). iPSC-TM decreased IOP by only 13%. In close correlation with IOP reduction, both treatments increased facility indicating restoration of function to conventional pathway (Fig 2A). Consistent with this observation, TM cellularity increased by up to ∼2.2-fold with hADMSC (Fig 2B).

Conclusions : Magnetically-steered hADMSC TM cell therapy significantly lowers IOP for 9 months in mice – outperforming iPSC-TM cell therapy. Magnetic steering used 30x fewer cells vs. a previous study without magnetic steering [4]. Preclinical studies with existing FDA-approved SPIONs are indicated.

References: [1] Bahranifard+, EER (2023; [2] Zode+, J Clin Inv (2011); [3] Sherwood+, PLoS1 (2016); [4] Zhu+, PNAS (2016)

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Fig 1. Measured IOPs (top) and facilities (bottom). White central band = mean; dark shading = 95% confidence interval (CI). Each dot is 1 eye (error bar = CI). * p < 0.05 with Bonferroni.

 

Fig 2. A) Measured vs. predicted IOPs. i) Regression plot (red = unity line). ii) Residuals (mean = dashed line, shading = CI). Color: groups as per Fig 1. B) TM cellularity. Colors denote sections from the same eye. LME, * p < 0.05 with Bonferroni.