Accumulative evidence has indicated that apoptosis is the common pathway for retinal ganglion cell (RGC) death and that autophagy promotes survival of RGCs in glaucoma. In the present review, it was hypothesized that the progressive death of RGCs in glaucoma involves another novel non‑apoptotic programmed cell death, known as 'paraptosis', in the early stages of glaucoma. Paraptosis may be accompanied by apoptosis and/or autophagy in the moderate and severe stages. The secondary hypothesis suggests that paraptosis in glaucomatous RGCs may be triggered by damage to cellular mitochondria, and is associated with mitochondria-derived reactive oxygen species (ROS). Our preliminary laboratory studies, using transmission electron microscopy, provided evidence that supports the primary hypothesis. The secondary hypothesis is currently under investigation. These two hypotheses provide a novel way to investigate the mechanisms of cell death in glaucomatous RGCs and targeting paraptosis may be a promising strategy for RGC-protecting drug discovery.

JOURNAL/nrgr/04.03/01300535-202310000-00037/figure1/v/2026-05-25T160659Z/r/image-tiff Mesenchymal stem cells have neuroprotective effects that limit damage to the retina and photoreceptors, and which may be mediated by extracellular vesicles (or exosomes) released by mesenchymal stem cells. To investigate the neuroprotective effect of extracellular vesicles derived from umbilical cord mesenchymal stem cells on glaucoma, we established rat models of chronic ocular hypertension by injecting conjunctival fibroblasts into the anterior chamber to mimic optic nerve injury caused by glaucoma. One week after injury, extracellular vesicles derived from umbilical cord-derived mesenchymal stem cells were injected into the vitreous cavity. We found that extracellular vesicles derived from mesenchymal stem cells substantially reduced retinal damage, increased the number of retinal ganglion cells, and inhibited the activation of caspase-3. These findings suggest that mesenchymal stem cell-derived extracellular vesicles can help alleviate optic nerve injury caused by chronic ocular hypertension, and this effect is achieved by inhibiting cell apoptosis.

Glaucoma is the leading cause of irreversible blindness worldwide, and pathologically elevated intraocular pressure (IOP) is the major risk factor. Neuroprotection is one of the potential therapies for glaucomatous retinal damage. Intravitreal mesenchymal stem cell (MSC) transplantation provides a viable therapeutic option, and human umbilical cord- (hUC-) MSCs are attractive candidates for cell-based neuroprotection. Here, we investigated the ability of transplanted hUC-MSCs to survive and migrate within the vitreous cavity and their neuroprotective effects on chronic glaucomatous retina. For this, we developed a chronic ocular hypertension (COH) rat model through the intracameral injection of allogeneic Tenon’s fibroblasts. Green fluorescent protein-transduced hUC-MSCs were then injected into the vitreous cavity one week after COH induction. Results showed that a moderate IOP elevation lasted for two months. Transplanted hUC-MSCs migrated toward the area of damaged retina, but did not penetrate into the retina. The hUC-MSCs survived for at least eight weeks in the vitreous cavity. Moreover, the hUC-MSCs were efficient at decreasing the loss of retinal ganglion cells; retinal damage was attenuated through the inhibition of apoptosis. In this study, we have developed a novel COH rat model and demonstrated the prolonged neuroprotective potential of intravitreal hUC-MSCs in chronic glaucoma.

The aim of the present study was to investigate the expression of leukemia inhibitory factor (LIF) and its downstream signaling pathways in the rat retina following acute ocular hypertension. The intraocular pressure of the rats was elevated to 110 mmHg for 1 h by infusing the anterior chamber with normal saline. The retinal tissues were obtained 12 h, 24 h, and 2, 3 and 7 days after termination of the ocular hypertension. Hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed to assess the morphological changes and the apoptosis of retinal cells, respectively. Quantification of the retinal ganglion cells (RGCs) was performed using fluorogold retrograde (FG) staining. The expression levels of LIF, LIF receptor (LIFR), signal transducers and activators of transcription 3 (STAT3), phosphorylated STAT3 (P‑STAT3), Akt, phosphorylated‑Akt (P‑Akt), extracellular signal‑regulated kinase (ERK) and phosphorylated ERK (P‑ERK) were determined at different time‑points following acute ocular hypertension using western blot analysis. Reverse transcription‑quantitative polymerase chain reaction was performned to detect the mRNA expression levels of LIF and LIFR. The results revealed that 12 h, 24 h, 2, 3 and 7 days after reperfusion, the thickness of the inner nuclear layer and the inner plexiform layer was decreased, with a significant reduction in the number of RGCs, as determined using TUNEL and FG staining. The expression levels of LIF and LIFR were increased following acute ocular hypertension. At 12 h post‑retinal reperfusion, the expression levels of P‑STAT3 and P‑Akt were significantly upregulated, while the expression of P‑ERK was decreased. The changes in the expression levels of LIF and LIFR suggested that LIF may be important in the process of degeneration/protection following retinal ischemia induced by acute ocular hypertension, via activation of the Janus kinase/STAT and Akt signaling pathways.