Abstract
Glaucoma is a leading cause of irreversible blindness. In this study, we investigated if transplanted stem cells are able to rescue a glaucoma mouse model with transgenic myocilin Y437H mutation and explored the possible mechanisms. Human trabecular meshwork stem cells (TMSCs) were intracamerally transplanted which reduced mouse intraocular pressure, increased outflow facility, protected the retinal ganglion cells and preserved their function. TMSC transplantation also significantly increased the TM cellularity, promoted myocilin secretion from TM cells into the aqueous humor to reduce endoplasmic reticulum stress, repaired the TM tissue with extracellular matrix modulation and ultrastructural restoration. Co-culturing TMSCs with myocilin mutant TM cells in vitro promoted TMSCs differentiating into phagocytic functional TM cells. RNA sequencing revealed that TMSCs had upregulated genes related to TM regeneration and neuroprotection. Our results uncovered therapeutic potential of TMSCs for curing glaucoma and elucidated possible mechanisms by which TMSCs achieve the treatment effect.
Highlights
Primary open-angle glaucoma (POAG), the most common type of glaucoma with a prevalence of 0.5–7.0% in adults, can result in damage of retinal ganglion cells (RGCs) and irreversible vision loss (Broman et al, 2008; Quigley, 2006)
To investigate therapeutic effect of Trabecular meshwork stem cells (TMSCs) on POAG, human TMSCs at passage three or four were injected into the anterior chamber of the Tg-MyocY437H mice (Figure 1—figure supplement 1) when they were at age of 4 months
Tg-MyocY437H mice transplanted with TMSCs started to lower intraocular pressure (IOP) from 1 month after stem cell transplantation, and IOP decreased to 13.30 ± 0.42 mmHg (Tg-TMSC) at 1 month
Summary
Primary open-angle glaucoma (POAG), the most common type of glaucoma with a prevalence of 0.5–7.0% in adults, can result in damage of retinal ganglion cells (RGCs) and irreversible vision loss (Broman et al, 2008; Quigley, 2006). Trabecular meshwork stem cells (TMSCs) have their special niche located at the anterior TM tissue beneath the Schwalbe’s line (Braunger et al, 2014; Raviola, 1982; Sundaresan et al, 2019; Yun et al, 2016) and have been successfully isolated and characterized (Castro and Du, 2019; Du et al, 2012). TMSCs exhibit the preference to home to the TM region in wild-type mice (Du et al, 2013) and to laser-damaged TM tissue, which is correlated with CXCR4/SDF1 chemokine
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