Stem cell transplantation rescued a primary open-angle glaucoma mouse model

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.

Stem cell-free therapy for glaucoma to preserve vision

“…Then we examined if TMSC secretome has protective roles to human TM cells in vitro. One of the characteristics of TM cells is that they are responsive to dexamethasone (Dex) treatment with increased intracellular myocilin expression 10,25,26 . Myocilin 27,28 and angiopoietin-like 7 (ANGPTL7) 22,29 are both glaucoma-associated markers.…”

“…To further confirm the TMSC-Scr therapeutic effects, we also investigated a genetic mouse model of glaucoma, the Tg-MyocY437H mice 10,20 , which start to have elevated IOP at 3-4-month of age. We periocularly injected 20 µl of 25x concentrated TMSC-Scr or 20 µl plain medium as sham control into the Tg-MyocY437H mice at 4-month of age (week-0) once a week until week-7 and sacrificed the mice at week-10 (Fig.…”

“…Similar to its effects to the Dex-Ac mice, treatment with TMSC-Scr significantly increased the TM cellularity in Tg-MyocY437H mice (17.5±1.1/TM). One feature of the Tg-MyocY437H mice is that mutant Myoc cannot be secreted out but stuck in the ER of TM cells leading to ER stress 10,20 . Indeed, we found an increased level of Myoc accumulated in the limbus tissue of the Tg-MyocY437H mice, which was reduced to the level as WT control after TMSC-Scr treatment as detected by staining (Fig.…”

“…Glaucoma progression is accompanied by increased loss of RGC at structural and functional level 43 . Pattern electroretinography (PERG) is an optimal approach to evaluate RGC function 10,44 . PERG shows that TMSC-Scr treatment preserved the RGC function of Tg-MyocY437H mice as indicated by increased amplitude of P1 wave (7.74±1.75 µV), similar to that of WT (7.76±1.14 µV), while the sham treatment could not recover P1 amplitude (4.05±1.95 µV), similar to that of untreated Tg-MyocY437H (5.86±2.24 µV) (Fig.…”

“…Our recent work has demonstrated that TMSC can impart therapeutic effects in glaucoma 9,10 . In this study, we explored the therapeutic effects of secretome derived from human TMSC (TMSC-Scr) with minimal invasive periocular injection in two mouse models of glaucoma: an ocular hypertension model induced by dexamethasone-acetate (Dex-Ac) periocular injection 19 and a transgenic open-angle glaucoma model with myocilin Y437H mutation (Tg-MyocY437H) 20 , and uncovered the potential mechanisms.…”