Excessive accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) leads to increased resistance to outflow of aqueous humor (AH) and the consequent increase in intraocular pressure (IOP) in primary open-angle glaucoma (POAG). Currently, there is no effective treatment to address this pathogenic mechanism of POAG. Therefore it is essential to screen for key proteins that are involved in TM ECM accumulation and further develop drugs targeting these mechanisms. Proteins were screened for significant up-regulation in TGFβ2-induced TM by label-free quantitative proteomics techniques. The relationship between TXNDC5 and ECM proteins was analyzed via qPCR, Western blot, and immunohistochemistry and validated in mice. Autophagy inhibitors (CQ) and protein synthesis inhibitors (CHX) were used, and molecular chaperone-mediated autophagy (CMA) activity was modulated to validate the degradation pathway-dependent mechanism of TXNDC5. We confirmed that in human TM cells, TXNDC5 contributed to the accumulation of ECM by increasing the expression of TGFβ R2. We also demonstrated that TXNDC5 was degraded through the CMA pathway, and that the AR7 was able to reverse TGFβ2-induced TM ECM accumulation. Most importantly, in vivo experiments have demonstrated that knockdown of TXNDC5 significantly reduced TGFβ2-induced ECM protein accumulation in TM tissues and reduces TGFβ2-induced ocular hypertension in the mouse. We revealed the role and probable mechanism by which TXNDC5 leads to TM ECM accumulation and IOP elevation, suggesting that targeting elevation of TXNDC5 is a potential new therapeutic approach to reduce TM ECM protein accumulation in POAG.

PRGF eye drops mitigate oxidative stress and fibrosis in an in vitro glaucoma model: The role of platelet and plasma enrichment.

Quantitative analysis of trabecular meshwork pigment after ICL implantation and influencing factors.

Anterior chamber tropism and systemic biodistribution of recombinant adeno-associated virus (rAAV) serotypes following intracameral injection.

Imaging the trabecular meshwork morphological changes in primary open angle glaucoma: An anterior segment OCT study.

Clinical effect of trabecular meshwork peeling in gonioscopy-assisted transluminal trabeculotomy (GATT).

PurposeWe have reported that trabecular meshwork stem cells (TMSCs) are effective for trabecular meshwork (TM) regeneration. This study aims to investigate different responses of TMSCs and TM cells to TGF-β2 and protective factors in TMSCs.MethodsHuman TMSCs and TM cells were exposed to TGF-β2 with or without antioxidant N-acetylcysteine, TMSC-derived secretome (TMSC-Scr), hepatocyte growth factor (HGF), or HGF receptor inhibitor (HGFI). Cell viability was assessed by the MTT assay. Intracellular reactive oxygen species (ROS) and lipid peroxidation were measured using CellROX and C11-BODIPY, respectively. Mitochondrial membrane potential was assessed using tetramethylrhodamine methyl ester (TMRM). Fibrotic markers (fibronectin, α-SMA, CTGF) were evaluated by immunofluorescent staining and Western blotting. RNA sequencing was performed to compare transcriptional profiles between TMSCs and TM cells. A cytokine array was used to compare TMSC-Scr and TM-Scr. A t-test or ANOVA followed by Tukey's multiple comparisons test was used for statistical analysis, with significance defined as P < 0.05.ResultsCompared with TM cells, TMSCs exhibited greater survival, better-preserved mitochondrial function, and lower levels of ROS, lipid peroxidation, and fibrotic marker expression after TGF-β2 treatment. N-acetylcysteine partially prevented TGF-β2 effects on TM cells. RNA sequencing and cytokine analyses identified significant enrichment of HGF in TMSCs and TMSC-Scr. TMSC-Scr and HGF markedly reduced oxidative and fibrotic responses to TGF-β2 in TM cells, whereas an HGFI abolished this protective effect.ConclusionsOur findings confirm that TMSC-Scr and HGF are promising candidates for cell-free therapies in glaucoma. HGF confers intrinsic resilience in TMSCs and functions as a key, but partial, mediator of their protection of TM cells.

Methylome profiling reveals epigenetic alterations in the trabecular meshwork of primary open-angle glaucoma.

Minimally Invasive Glaucoma Surgery in the Surgical Landscape of Primary Angle Closure Glaucoma: Current Innovations and Future Trends.

Resident tissue macrophages maintain intraocular pressure homeostasis.

Background: The Kahook Dual Blade (KDB) is a minimally invasive glaucoma surgery (MIGS) device designed to excise a strip of trabecular meshwork, enhancing aqueous outflow via Schlemm’s canal. While its efficacy is well-documented, there is limited evidence comparing outcomes between anatomical quadrants treated. Objectives: To compare intraocular pressure (IOP) reduction, medication burden, visual acuity improvement, and complication rates between nasal and inferior quadrant sectoral excisional goniotomy with KDB combined with cataract surgery. Design: Retrospective cohort study. Methods: Medical records of patients with primary open-angle glaucoma who underwent combined phacoemulsification and KDB goniotomy between January 2020 and June 2025 at a single tertiary academic center were reviewed. Patients were grouped by treatment location (nasal vs inferior). Primary outcomes were IOP and the number of glaucoma medications; secondary outcomes included best-corrected visual acuity (BCVA) and adverse events. Multivariate linear regression was used to adjust for baseline differences between groups. Results: Sixty-four eyes (nasal: 50; inferior: 14) met the inclusion criteria. Baseline IOP and BCVA were similar between groups, though the inferior group had fewer medications (1.93 vs 2.68; p = 0.045) and milder visual field loss (MD −8.39 vs −15.18; p = 0.04). Mean treatment extent was approximately 90° in both groups. Both groups achieved significant IOP reduction at all follow-up points, with no long-term differences. At postoperative week 1, the inferior group had higher IOP (18.50 vs 13.99 mmHg; p = 0.0433), potentially due to gravity-dependent hyphema. Medication burden decreased in both groups, with a non-significant trend toward fewer drops in the inferior group. BCVA improved similarly, and complication rates were low and comparable, with no serious adverse events. Conclusion: Nasal and inferior quadrant KDB goniotomy combined with cataract surgery yields comparable long-term outcomes in IOP, medication burden, visual acuity, and safety. Quadrant selection may be guided by intraoperative visualization and patient-specific anatomy without compromising efficacy.

This study aimed to evaluate the therapeutic potential of trabecular meshwork stem cells (TMSC) transplantation in enhancing the trabecular meshwork (TM) cell proliferation and intraocular pressure (IOP) reduction in a cell loss human organ cultured anterior segment (HOCAS) model of glaucoma. A cell loss HOCAS model of glaucoma was established using saponin. IOP was monitored at regular intervals, and immunohistochemistry was performed to quantify the cell loss. Qtracker-labeled cultured TMSCs (3 × 10⁵ cells/500µl) were transplanted into the model, with periodic monitoring of IOP changes. After five days of transplantation, tissues were subjected to immunohistochemistry (ABCG2, p75) to evaluate the localization of the transplanted stem cells. The effectiveness of the transplanted cells in promoting TM proliferation was further evaluated by Ki67 staining. The saponin treatment in the HOCAS model resulted in 32.08 ± 4.74% cell death and decrease in the outflow facility by 15% at day 6. Transplantation of cultured TMSCs into this model mitigated the outflow resistance induced by saponin and increase the outflow by 38%. Confocal microscopic analysis confirmed the homing of transplanted TMSCs to both filtering and non-filtering regions of the TM. Additionally, TMSC transplantation resulted in a significant increase in TM cell proliferation, which was 17.94 ± 4.45% compared to the sham treatment, which showed 5.29 ± 4.2%. The cell loss HOCAS model for glaucoma was established using saponin which resulted in IOP increase and TM cell loss. Further, in this model, the transplanted TMSCs, home to TM, and resulted in the reduction of IOP which was increased upon saponin treatment. The TMSC transplantation also enhanced TM cell proliferation.

PurposeTo evaluate antioxidant capacity in aqueous humor (AH), trabecular meshwork (TM), and lens epithelium (LE) from patients with primary open-angle glaucoma and cataract and to assess associations with race and disease severity.MethodsIn this prospective cross-sectional study, two surgical cohorts undergoing cataract with glaucoma surgery provided either AH or paired TM/LE. AH total reactive antioxidant potential and ascorbic acid were measured. In paired TM and LE from the same eye, qPCR assessed nuclear factor erythroid 2–related factor 2 (NRF2), catalase (CAT), and superoxide dismutase 2. For AH, group comparisons used Welch's t tests or Mann–Whitney tests, and severity-stratified analyses used Race × Severity two-way ANOVA with Šídák correction. For qPCR, within-eye differences were calculated as Δ(TM − LE); race comparisons used Welch's t tests for each marker, with Šídák correction across the three markers.ResultsAH was analyzed from 106 eyes (Black n = 37; White n = 69); no race differences remained after Race × Severity modeling with Šídák adjustment. Paired TM/LE qPCR was analyzed from 42 eyes (Black n = 21; White n = 21). In Black eyes, NRF2 and CAT were lower in TM relative to matched LE (both P < 0.0001), whereas no such paired tissue differences were detected in White eyes. The within-eye difference Δ(TM − LE) was more negative in Black than White eyes for NRF2 (P = 0.0001) and CAT (P = 0.0024). Superoxide dismutase 2 showed no race-associated difference.ConclusionsAH antioxidant measures showed limited race-associated differences, whereas paired TM/LE profiling revealed tissue- and marker-specific expression differences most evident in Black patients. These compartment-specific signatures warrant validation in larger prospective cohorts.

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness, has a strong genetic basis. The Primary Open-Angle African Ancestry Glaucoma Genetics study previously identified 46 risk loci. To pinpoint causal variants and their corresponding effector genes, we analyzed gene expression, chromatin accessibility, and conformation in two ocular cell-types: trabecular meshwork cells (hTMCs) and retinal ganglion cells derived from induced pluripotent stem cells (hiPSC-RGCs). We identified 24 candidate genes in hTMCs and 56 in hiPSC-RGCs. TheARHGEF12gene was selected for further validation because it was nominated by local and distal promoter interactions in both cell-types and has reproducible prior evidence of its association with POAG. While its role in hTMCs is established, its function in RGCs is unclear. hiPSC-RGCs generated from a POAG donor homozygous for the risk allele showed reducedARHGEF12expression, altered morphology, and disrupted neuronal activity. This framework enables functional evaluation of additional POAG risk variants.

Implantable Collamer Lens (ICL) implantation is an effective treatment for correcting high hyperopia. However, late anterior segment complications remain insufficiently characterized. The simultaneous occurrence of angle narrowing, pigment dispersion, and intraocular pressure (IOP) elevation nearly two decades after implantation of a non-central-port ICL is exceptionally rare. This case illustrates the diagnostic and surgical challenges of late-onset angle narrowing in hyperopic eyes and outlines strategies to minimize iris injury during ICL explantation. A 38-year-old woman presented with progressive bilateral elevation of IOP occurring 15 years after implantation of non-central-port ICLs for high hyperopia. Slit-lamp examination revealed shallow anterior chambers with patent peripheral iridotomies, narrow angles with partial peripheral anterior synechiae, and pronounced pigment deposition on the corneal endothelium, ICL surfaces, and trabecular meshwork. Sequential ICL explantation combined with cataract extraction and posterior chamber intraocular lens implantation was performed. During surgery on the left eye, mechanical iris trauma resulted in a sectoral iris defect causing monocular diplopia and photic disturbances. Despite undergoing iris repair, the patient’s photic symptoms did not improve. In the right eye, preoperative cycloplegia and intravenous mannitol deepened the anterior chamber and prevented iris injury. Postoperatively, both eyes developed a transient fibrin reaction that resolved with topical anti-inflammatory therapy. At the 6-month follow-up, IOP and visual acuity remained stable in both eyes, although mild glare sensitivity persisted. This case demonstrates that late-onset angle closure and pigment dispersion can occur after ICL implantation, particularly in highly hyperopic eyes with shallow anterior chambers. Lifelong monitoring of anterior chamber configuration and IOP is therefore essential in these patients. When IOP elevation secondary to angle closure develops, combined ICL explantation and cataract surgery can effectively restore aqueous outflow and visual function. Adequate preoperative deepening of the anterior chamber and avoidance of intraoperative iris manipulation are critical to minimize postoperative dysphotopsia and monocular diplopia.

Pseudoexfoliation syndrome is a common age-related disorder characterized by the accumulation of extracellular fibrillar material in various systemic and ocular tissues, particularly on the lens capsule, iris, and trabecular meshwork. The prevalence of pseudoexfoliation syndrome varies worldwide due to differences in geographic location, ethnic background, and environmental factors. This condition has a significant impact on ocular health, particularly among older adults, as it can complicate cataract surgery and is associated with severe forms of glaucoma that are often difficult to manage. A hospital-based retrospective cross-sectional study was conducted at Debre Markos and Felege Hiwot comprehensive specialized hospitals. The study reviewed medical records of cataract patients aged 40 years and above who attended the hospitals from January to July 2023. All consecutive eligible records were included. Data were extracted using a structured data extraction tool from June 12 to July 12, 2023. A total of 880 medical records of cataract patients were analyzed. The median age of the participants was 68 years, with an interquartile range of 18. The overall proportion of pseudoexfoliation syndrome was 38%. Factors independently associated with pseudoexfoliation syndrome included outdoor activity (AOR = 6.75, 95% CI 1.99, 8.35), older age (AOR = 5.50, 95% CI 3.75, 8.95), hypertension (AOR = 4.00, 95% CI 2.56, 5.98), glaucoma (AOR = 4.00, 95% CI 2.33, 7.39), nuclear cataract (AOR = 3.98, 95% CI 2.01, 8.94), rural residence (AOR = 3.80, 95% CI 1.99, 6.44), male patients (AOR = 2.01, 95% CI 1.44, 6.43) and high intraocular pressure (AOR = 1.5, 95% CI 1.25, 8.00). The prevalence of pseudoexfoliation syndrome among cataract patients in this study was relatively high. The condition was more frequently observed among participants aged 40 years and above. The findings may contribute to the understanding of pseudoexfoliation syndrome in cataract patients.

Purpose.Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in many inflammatory and fibrotic diseases; however, its role in primary open-angle glaucoma (POAG) and trabecular meshwork (TM) dysfunction remains unknown. In this study, we investigated whether MIF-CD74 signaling regulates TM pathobiology through modulation of the transcription factor, Blimp-1, and downstream cytoskeletal reorganization and extracellular matrix (ECM) remodeling.Method.Primary human TM cells (HTMC) were exposed to glaucomatous stressors, including TGF-β2, rMIF, or a pro-inflammatory milieu. Expression of MIF, its receptor CD74, and Blimp-1 was measured by qPCR and immunoblotting. ECM proteins and phosphorylated myosin-light chain (pMLC) were evaluated by immunofluorescence staining. In vivo, MIF-CD74 and Blimp-1 expression were examined in the TM/anterior segment (AS) tissue of Tg.CreMYOCY437H and lentiviral (LV)-TGF-β2-induced ocular hypertension (OHT) mouse models. Functional involvement of MIF signaling in TM pathobiology was examined using the irreversible MIF inhibitor 4-IPP and the immunomodulatory metabolites agmatine and thiamine.Results.Glaucomatous stressors significantly upregulated MIF and CD74 expression with concomitant suppression of Blimp-1 in HTMC. Similarly, TM/AS tissue from both OHT models (Tg.CreMYOCY437H and LV-TGF-β2) demonstrated increased MIF-CD74 expression accompanied by reduced Blimp-1 levels. Activation of MIF-CD74 signaling triggered pro-inflammatory and cell death pathways and promoted ECM remodeling, characterized by increased fibrotic protein expression and enhanced RhoA/ROCK-mediated MLC phosphorylation, indicating modulation of TM contractility. Pharmacological inhibition of MIF attenuated inflammatory signaling, reduced ECM deposition and cytoskeletal remodeling, and suppressed RhoA/ROCK/MLC activation, restoring a protective TM phenotype.Conclusion.Our findings identify MIF-CD74 signaling as a previously unrecognized regulator of TM dysfunction in POAG. MIF-mediated suppression of Blimp-1 mechanistically links inflammatory signaling to cytoskeletal contractility and fibrotic ECM remodeling, key determinants of aqueous humor outflow resistance. Targeting the MIF-CD74/Blimp-1 axis may represent a novel therapeutic strategy to restore TM homeostasis and reduce intraocular pressure in glaucoma.

The trabecular meshwork (TM) plays a pivotal role in maintaining intraocular pressure (IOP) by regulating aqueous humor outflow. Nuclear factor erythroid 2-related factor 2 (NRF2) was identified as a key transcriptional controller of TM redox balance and mitochondrial function. Transcriptomic profiling of tert-butyl hydroperoxide (tBHP)-induced oxidative injury revealed NRF2 pathway involvement in TM cellular defense. NRF2 knockout (KO) mice exhibited impaired aqueous humor dynamics, elevated IOP, and TM oxidative damage. In vitro, NRF2 knockdown aggravated oxidative stress and mitochondrial dysfunction, whereas NRF2 overexpression mitigated tBHP-induced cytotoxicity. The results of the gene set enrichment analysis (GSEA) indicated enrichment of oxidative phosphorylation pathway in NRF2-deficient cells. Chromatin immunoprecipitation sequencing (ChIP-seq) confirmed NDUFS7 as a direct NRF2 target essential for mitochondrial complex I integrity. Restoration of NDUFS7 expression in NRF2-deficient TM cells or KO mice rescued mitochondrial impairment. Collectively, these findings establish the NRF2/NDUFS7 axis as a central defense mechanism protecting TM from oxidative injury and suggest potential therapeutic strategies for glaucoma-associated ocular hypertension.

Glaucoma trabecular meshwork (GTM) cells cultured in vitro retain many characteristics of their in situ phenotype. Here, we used isobaric tandem mass tags (TMTpro) to label peptides from glaucomatous and non-glaucomatous TM (NTM) cells to identify differentially regulated proteins. Confluent NTM (n = 5) and GTM (n = 5) cells were lysed, proteins were trypsin digested, and peptides were labeled with 18-plex TMTpro. TMT-labeled peptides were fractionated on an Orbitrap Fusion mass spectrometer and data were processed using the PAW/Comet pipeline and EdgeR with Benjami–Hochberg multiple correction testing. Isobaric multiplexed quantitative proteomics identified 206 proteins that were significantly (FDR < 0.1) upregulated in GTM cells, 42 proteins that were downregulated, with 5270 non-candidates. Significant regulated pathways included extracellular matrix (DCN, COL4A1, CHI3L1), Wnt signaling (FZD1, FZD7, GSK3B), cytoskeletal regulation (ROCK2, MSN, TPM2, VIM, NF2), protein degradation (USP9X, LAMP1, SYNV1, UBE2L3), and nuclear proteins (LMNA, DFFA, CHMP3, RAD21). Western immunoblotting studies confirmed the TMTpro data. Immunofluorescence showed that the SNX7-stained nucleoli of GTM cells were significantly (p < 0.05) larger, and the DIAPH2 immunostaining was more distended into the cytosol than in NTM cells. This study identified many significantly regulated proteins in cultured GTM cells, and the results revealed several new avenues for developing clinical therapies for glaucoma patients.

SUMMARYPrimary open-angle glaucoma (POAG) is a chronic neurodegenerative disorder, and elevated intraocular pressure (IOP) represents the major, and only modifiable, risk factor for the disease. We modeled increased IOP by treating three primary human trabecular meshwork (TM) cell strains with dexamethasone, then generated a high-resolution map of promoter-centered chromatin contacts and regulatory modules to decipher how the genomic architecture and epigenetic state of disease-associated loci contribute to pathogenesis. We identify dynamic changes in chromatin compartments and looping, cis-regulatory elements and transcription factor hubs corresponding to altered transcriptional profile. By integrating GWAS-associated variants with dexamethasone-induced 3D chromatin landscape, we discovered 26 IOP- and 52 POAG- candidate causal genes, which belong to vesicle transport, TLR, MAPK and hippo-YAP signaling pathways. We also uncovered transcriptional regulatory role of 103 non-coding lead variants. Our studies provide a mechanistic framework of genetic complexity associated with ocular hypertension and POAG pathogenesis in addition to targets for therapies.