Enhanced immunosuppressive capability of mesenchymal stem cell-derived small extracellular vesicles with high expression of CD73 in experimental autoimmune uveitis.

BACKGROUND: Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. METHODS: To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. RESULTS: Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. CONCLUSION: Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.

Optical coherence tomography biomarkers as outcome predictors to guide dexamethasone implant use in patients with iERM: a randomized controlled trial.

BACKGROUND: We aimed to investigate the anatomical features of optical coherence tomography (OCT) and vitreous cytokine levels as predictors of outcomes of combined phacovitrectomy with intravitreal dexamethasone (DEX) implants for idiopathic epiretinal membrane (iERM) treatment. METHODS: A prospective, single-masked, randomized, controlled clinical trial included 48 eyes. They were randomly assigned in a 1:1 ratio to undergo the DEX group (combined phacovitrectomy with ERM peeling and Ozurdex implantation) and control group (phacovitrectomy only). Best-corrected visual acuity (BCVA) and central macular thickness (CMT) were assessed at 1 d, 1 week, 1 month, and 3 months. The structural features of OCT before surgery were analysed for stratified analysis. Baseline soluble CD14 (sCD14) and sCD163 levels in the vitreous fluid were measured using ELISA. RESULTS: BCVA and CMT were not significantly different in the DEX and control groups. Eyes with hyperreflective foci (HRF) at baseline achieved better BCVA (Ptime*group=0.746; Pgroup=0.043, Wald χ²=7.869) and lower CMT (Ptime*group = 0.079; Pgroup = 0.001, Wald χ²=6.774) responses to DEX during follow-up. In all patients, the mean vitreous level of sCD163 in eyes with HRF was significantly higher than that in eyes without HRF (P = 0.036, Z=-2.093) at baseline. In the DEX group, higher sCD163 predicted greater reduction in CMT from baseline to 1 month (r = 0.470, P = 0.049). CONCLUSIONS: We found that intraoperative DEX implantation did not have beneficial effects on BCVA and CMT over a 3-month period in all patients with iERM, implying that the use of DEX for all iERM is not recommended. In contrast, for those with HRF on OCT responded better to DEX implants at the 3-month follow-up and thier vitreous fluid expressed higher levels of sCD163 at baseline. These data support the hypothesis that DEX implants may be particularly effective in treating cases where ERM is secondary to inflammation. TRIAL REGISTRATION: The trail has been registered at Chinese Clinical Trail Registry( https://www.chictr.org.cn ) on 2021/03/12 (ChiCTR2100044228). And all patients in the article were enrolled after registration.

Effectiveness of toric intraocular lens implantation for correcting irregular corneal astigmatism in cataract eyes.

A retrospective cohort study was conducted to observe the correction effect of Toric intraocular lens (IOL) implantation in cataract eyes with specific types of irregular corneal astigmatism. Thirty-four eyes with either the "asymmetric bow-tie" pattern (Type I) or the "angled bow-tie" pattern (Type II) were included. Corneal topography was assessed using Pentacam HR, and changes in preoperative corneal astigmatism, visual acuity, manifest refraction, and objective visual quality were measured and compared. The average uncorrected distance visual acuity improved significantly from 0.86 ± 0.40 logMAR to 0.22 ± 0.15 logMAR (P < 0.001). Preoperative corneal astigmatism of 2.05 ± 0.90 D was corrected to a postoperative residual astigmatism of 0.78 ± 0.57 D (P < 0.001), with 32% of eyes within 0.50 D. The residual astigmatism prediction errors in Type I and Type II cases were (0.97 ± 0.68 D) and (0.66 ± 0.37 D), respectively (P = 0.100). The mean spherical equivalent prediction error in Type II cases (0.07 ± 0.36 D) was significantly smaller than that in Type I cases (- 0.29 ± 0.52 D) (P = 0.030). This study concludes that Toric IOL implantation effectively corrects specific types of irregular corneal astigmatism in cataract surgery. Eyes with the "angled bow-tie" pattern show higher accuracy in refractive predictions compared to eyes with the "asymmetric bow-tie" pattern.

The Anatomic and Functional Outcomes of Ozurdex-Aided Vitrectomy in Proliferative Diabetic Retinopathy.

Purpose: To investigate the 3-months outcomes of patients who underwent intraoperative intravitreal injection of Ozurdex for proliferative diabetic retinopathy (PDR). Methods: This is a prospective randomized controlled clinical trial (ChiCTR2100043399). Seventy-one patients with PDR who had indications for surgery without intravitreal injection history within 3 months preoperatively were enrolled. Patients were randomly divided into three groups based on the medicine injected intraoperatively: Ozurdex, Conbercept, and Control group. The primary outcome is the best-corrected visual acuity (BCVA) within 3 months postoperatively. The secondary outcomes include the intraocular pressure (IOP), mean sensitivity, central retinal thickness and vessels perfusion. Results: The BCVA and the mean sensitivity improved in the three groups (F = 130.8, P < 0.0001; F = 34.18, P < 0.0001), but there was no statistical difference among the three groups (F = 0.858, P = 0.552; F = 0.964, P = 0.452). The IOP was no significant differences among the three groups within 3 months postoperatively (F = 0.881, P = 0.533). Compared with the other two groups, central retinal thickness (CRT) and outer retinal layer (ORL) thickness decreased significantly in patients of the Ozurdex group (F = 3.037, P = 0.008; F = 2.626, P = 0.018), especially in the diabetic macular edema (DME) patients (F = 2.761, P = 0.0164; F = 2.572, P = 0.0240). In macular region, superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) perfusion were not shown statistical difference at 3 months postoperatively in the all three groups compared with 1 day postoperatively (P > 0.05). Conclusion: Compared with the other two groups, anatomical outcomes was improved significantly in Ozurdex group for DR patients. Ozurdex may help to improve the visual acuity and visual sensitivity, and there is no significant difference in the change of IOP and microvascular improvement. Clinical Trial Registration: This trial is registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn, registration number ChiCTR2100043399).

Comparison of two objective methods for measuring postoperative toric intraocular lens orientation under the natural pupil.

PURPOSE: To evaluate and compare the accuracy of iTrace and CASIA2 in measuring the postoperative orientation of toric intraocular lens (IOL) without mydriasis. SETTING: Tianjin Medical University Eye Hospital, Tianjin, China. DESIGN: Prospective cohort study. METHODS: Patients with SN6AT toric IOLs implanted after cataract surgery were enrolled. 1 month after surgery, the toric IOL orientation were measured by iTrace and CASIA2 in non-mydriatic, semi-dark conditions. Then, the toric axis was directly reviewed using the slit-lamp under full mydriasis. Axis measurement differences between each of the 2 devices and the slit-lamp, described as their relative differences (RDs), were calculated and compared. The percentage of RDs within 5 degrees, within 10 degrees and greater than 30 degrees were analyzed. RESULTS: 77 eyes of 70 patients were included. Generally, the mean toric axis measurement RDs of CASIA2 and iTrace were 9.24 ± 10.53 degrees and 13.89 ± 15.47 degrees respectively ( P = .04). For CASIA2 (72 eyes), 54.17% (39), 72.22% (52), and 4.17% (3) of eyes had RDs within 5 degrees, within 10 degrees and greater than 30 degrees, compared with 40.00% (28), 61.43% (43) and 12.86% (9) for iTrace (70 eyes). The 95% limits of agreements of CASIA2 with slit-lamp was narrower than that of iTrace with slit-lamp. The median RD of CASIA2 was significantly smaller in eyes with pupil ≥4 mm under dark condition compared with eyes with pupil <4 mm ( P = .03). CONCLUSIONS: CASIA2 demonstrates greater precision in measuring toric IOL orientation under non-mydriatic conditions compared with iTrace. Moreover, the accuracy of CASIA2 is enhanced in cases of pupil >4 mm.

Plasmin-Induced Lens Epithelial Cells Detachment for the Reduction of Posterior Capsular Opacification.

Purpose: We sought to evaluate the efficacy and safety of plasmin injection in the capsular bag during the cataract operation for the prevention of posterior capsule opacification. Methods: Thirty-seven anterior capsular flaps taken from phacoemulsification surgery were immersed in either 1 µg/mL plasmin (plasmin group, n = 27) or phosphate-buffered saline (control group, n = 10) for 2 minutes and photographed after fixation and nuclear staining to compare the numbers of residual lens epithelial cells. In the animal experiments, the plasmin solution was injected into the capsular bag and remained for 5 minutes during hydrodissection or after lens extraction. The degree of posterior capsular opacity of the rabbits at 2 months were photographed by slit lamp biomicroscopy. In HLE-B3 cell culture, the cell detachment rate, proliferation, and apoptosis after the plasmin digestion were analyzed. Results: The residual lens epithelial cell numbers on the capsule after plasmin treatment were 168 ± 190.7/mm2 in the 1 µg/mL plasmin group, which was significantly lower than that of the control (1012 ± 798.8/mm2; P < 0.0001). In a rabbit model, the treatment of plasmin resulted in a significantly clearer posterior capsule compared with that of the control group at 2 months postoperatively. Conclusions: This study suggested that plasmin injection can induce effective lens epithelial cell detachment, which could be a promising adjunctive treatment to further improve the success rate in posterior capsule opacification prevention. Translational Relevance: Plasmin injection for lens epithelial cell detachment could significantly decrease the number of residual lens epithelial cells. This approach could be a promising treatment incorporating the current treatment approach to further improve the success rate in posterior capsule opacification prevention.

Mesenchymal-Stem-Cell-Based Strategies for Retinal Diseases.

Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies. However, hindered by the retinal barriers, the initial vision for the stem cell replacement strategy fails to achieve the anticipated effect and has now been questioned. Accumulating evidence now suggests that the paracrine effect may play a dominant role in MSC-based treatment, and MSC-derived extracellular vesicles emerge as a novel compelling alternative for cell-free therapy. This review summarizes the therapeutic potential and current strategies of this fascinating class of cells in retinal degeneration and other retinal dysfunctions.

Effects of nanoscale zero-valent iron on the performance and the fate of antibiotic resistance genes during thermophilic and mesophilic anaerobic digestion of food waste.

The effects of nanoscale zero-valent iron (nZVI) on the performance of food waste anaerobic digestion and the fate of antibiotic resistance genes (ARGs) were investigated in thermophilic (TR) and mesophilic (MR) reactors. Results showed that nZVI enhanced biogas production and facilitated ARGs reduction. The maximum CH4 production was 212.00 ±â€¯4.77 ml/gVS with 5 g/L of nZVI in MR. The highest ARGs removal ratio was 86.64 ±â€¯0.72% obtained in TR at nZVI of 2 g/L. nZVI corrosion products and their contribution on AD performance were analyzed. The abundance of tetracycline genes reduced significantly in nZVI amended digesters. Firmicutes, Chloroflexi, Proteobacteria and Spirochaetes showed significant positive correlations with various ARGs (p < 0.05) in MR and TR. Redundancy analysis indicated that microbial community was the main factor that influenced the fate of ARGs. nZVI changed microbial communities, with decreasing the abundance bacteria belonging to Firmicutes and resulting in the reduction of ARGs.

CD73 Pathway Contributes to the Immunosuppressive Ability of Mesenchymal Stem Cells in Intraocular Autoimmune Responses.

Mesenchymal stem cells (MSCs) exhibit a potent immunomodulatory capacity and have been applied to treat diseases such as graft versus host disease and severe autoimmune diseases. However, the mechanism underlying their immunosuppressive effect is not yet completely understood. Here, we investigated the role of the CD73/adenosine pathway in immune modulation by MSCs using a mouse model of experimental autoimmune uveitis (EAU). Moreover, we examined the in vitro modulatory effect of MSCs mediated through the CD73/adenosine pathway in human and mouse T cells. We found that the severity of EAU was significantly attenuated by MSCs; however, most therapeutic effects of MSCs were lost by pretreatment with a CD73 inhibitor. The inhibitory mechanism of MSCs might be contributed by CD73 on MSCs that cooperated with CD39 and CD73 on activated T cells to produce adenosine, resulting in inhibition of T-cell proliferation. Furthermore, MSCs increased the expression of CD73 on CD4(+) T cells, and transforming growth factor-ß1 (TGF-ß1) was the only tested cytokine that contributed to upregulation of CD73. Hence, our study demonstrates that the CD73/adenosine pathway involves the immunomodulatory function of MSCs in autoimmune responses.