Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases.

Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton Jelly. Although cell-mediated mechanisms have been reported, the therapeutic effect of MSCs is now recognized to be primarily mediated via paracrine effects through the secretion of bioactive molecules, known as the "secretome". The regenerative benefit of the secretome has been attributed to trophic factors and cytokines that play neuroprotective, anti-angiogenic/pro-angiogenic, anti-inflammatory, and immune-modulatory roles. The advancement of autologous MSCs therapy can be hindered when introduced back into a hostile/disease environment. Barriers include impaired endogenous MSCs function, limited post-transplantation cell viability, and altered immune-modulatory efficiency. Although secretome-based therapeutics have gained popularity, many translational hurdles, including the heterogeneity of MSCs, limited proliferation potential, and the complex nature of the secretome, have impeded the progress. This review will discuss the experimental and clinical impact of restoring the functional capabilities of MSCs prior to transplantation and the progress in secretome therapies involving extracellular vesicles. Modulation and utilization of MSCs-secretome are most likely to serve as an effective strategy for promoting their ultimate success as therapeutic modulators.

Toll-like receptor-4 knockout mice are more resistant to optic nerve crush damage than wild-type mice.

BACKGROUND: This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4-/-) compared to wild-type (WT) mice. METHODS: ONC was induced in TLR4-/- and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-α) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b. RESULTS: There was a 25.5% and 38% loss in the RGC layer of the ONC-injured eyes of the TLR4-/- and the WT mice, respectively (with 27% and 9% of the remaining cells positive for Brn3a, respectively). Mean levels of Thy-1 and Brn3b were higher in the TLR4-/- mice. CD45 and Iba1 staining revealed infiltration of inflammatory cells into the injured nerve and retina in both groups. Molecular analysis of the optic nerve on day 1 showed increased TNF-α expression and reduced CD45 and GFAP expression; on day 3, CD45 reverted to baseline but GFAP remained low; on day 21, all 3 markers were at baseline in the TLR4-/- group and decreased in the WT group. CONCLUSION: Inflammation plays a major role in the response to ONC injury. Reduced levels of inflammation are associated with improved RGC preservation. The increase in TNF-α and reduction in CD45 in both TLR4-/- and WT mice may indicate the presence of an alternative pathway for induction of RGC death.

Stem cell factor protects against chronic ischemic retinal injury by modulating on neurovascular unit.

Retinal ischemia is a significant factor in various vision-threatening diseases, but effective treatments are currently lacking. This study explores the potential of stem cell factor (SCF) in regulating the neurovascular unit as a therapeutic intervention for retinal ischemic diseases. A chronic retinal ischemia model was established in Brown Norway rats using bilateral common carotid artery occlusion (BCCAO). Subsequent SCF treatment resulted in a remarkable recovery of retinal function, as indicated by electroretinogram, light/dark transition test, and optokinetic head tracking test results. Histological examination demonstrated a significant increase in the number of retinal neurons and an overall thickening of the retina. Immunofluorescence confirmed these findings and further demonstrated that SCF treatment regulated retinal remodeling. Notably, SCF treatment ameliorated the disrupted expression of synaptic markers in the control group's BCCAO rats and suppressed the activation of Müller cells and microglia. Retinal whole-mount analysis revealed a significant improvement in the abnormalities in retinal vasculature following SCF treatment. Transcriptome sequencing analysis revealed that SCF-induced transcriptome changes were closely linked to the Wnt7 pathway. Key members of the Wnt7 pathway, exhibited significant upregulation following SCF treatment. These results underscore the protective role of SCF in the neurovascular unit of retinal ischemia rats by modulating the Wnt7 pathway. SCF administration emerges as a promising therapeutic strategy for retinal ischemia-related diseases, offering potential avenues for future clinical interventions.

A retrospective study of ophthalmologic presentation, management, and outcomes in pediatric patients admitted with abusive head trauma.

Background: Abusive head trauma (AHT) is a severe form of physical abuse leading to significant morbidity and mortality in children, often presenting with complex brain injuries. Among the varied manifestations, ophthalmologic presentations are critical yet underexplored, which may provide essential clues for early diagnosis and management, improving long-term visual and neurological outcomes. Objective: This study aims to explore the manifestation, management, and outcomes of AHT cases within a single center in China over a five-year period, with a focus on the importance of ophthalmologic evaluation in enhancing the diagnosis, management, and outcome predictions of AHT. Methods: A retrospective case series was conducted at a single institution, involving infants diagnosed with AHT from 2019 to 2023. Data on demographics, medical histories, and clinical management were collected. Ophthalmologic examinations including fundus photography, ocular B-scan ultrasound and fundus fluorescein angiography (FFA), were performed to evaluate retinal vasculature and identify peripheral ischemic retina (PIR). Statistical analyses were performed using SPSS ver. 26.0. Results: Eight AHT patients (16 eyes) were included in the study. Bilateral ocular involvement was observed in all patients, with 81.25% exhibiting retinal hemorrhages (RH). Other manifestations included retinal detachment (31.25%) and optic nerve atrophy (18.75%). Clinical interventions varied, with 68.75% of patients undergoing treatments such as laser photocoagulation and anti-vascular endothelial growth factor (VEGF) injections. Among all eyes, 75% showed resolution of RH. Despite treatment, some patients progressed to severe conditions such as retinal detachment (RD) and iris neovascularization (INV). Conclusion: This study emphasizes the importance of a multidisciplinary approach in the diagnosis and management of AHT, particularly by integrating ophthalmological perspectives into patient care. These findings contribute to the understanding of ophthalmologic presentations in AHT.

Bilateral Ischemic Retinopathy Associated With Upshaw-Schulman Syndrome: A Case Report.

Purpose: This is the first report to our knowledge of ischemic retinopathy in a pediatric patient with Upshaw-Schulman syndrome (USS). Methods: A 6-year-old girl previously diagnosed with USS was referred to our clinic with exodeviation of the left eye and a 2-month-long decrease in vision of both eyes. A dilated fundus examination showed a total vitreous hemorrhage in both eyes. The first course of action was conservative treatment, with the patient experiencing visual-acuity improvement in her right eye. Results: An ischemic retina and optic nerve atrophy was found once the left eye was cleared of the hemorrhage. Conclusions: We present a case of a vitreous hemorrhage, possibly secondary to an episode of severe thrombocytopenia. Following USS diagnosis, providers should perform dilated ophthalmologic examinations as part of initial and follow-up general evaluations. This case exemplifies that, in understudied and underdescribed pediatric retinal diseases, extreme therapeutic decisions-such as surgery-should not be rushed.

Detection of retinal capillary nonperfusion in fundus fluorescein angiogram of diabetic retinopathy.

INTRODUCTION: Retinal capillary nonperfusion (CNP) is one of the retinal vascular diseases in diabetic retinopathy (DR) patients. As there is no comprehensive detection technique to recognize CNP areas, we proposed a different method for computing detection of ischemic retina, non-perfused (NP) regions, in fundus fluorescein angiogram (FFA) images. METHODS: Whilst major vessels appear as ridges, non-perfused areas are usually observed as ponds that are surrounded by healthy capillaries in FFA images. A new technique using homomorphic filtering to correct light illumination and detect the ponds surrounded in healthy capillaries on FFA images was designed and applied on DR fundus images. These images were acquired from the diabetic patients who had referred to the Nikookari hospital and were diagnosed for diabetic retinopathy during one year. Our strategy was screening the whole image with a fixed window size, which is small enough to enclose areas with identified topographic characteristics. To discard false nominees, we also performed a thresholding operation on the screen and marked images. To validate its performance we applied our detection algorithm on 41 FFA diabetic retinopathy fundus images in which the CNP areas were manually delineated by three clinical experts. RESULTS: Lesions were found as smooth regions with very high uniformity, low entropy, and small intensity variations in FFA images. The results of automated detection method were compared with manually marked CNP areas so achieved sensitivity of 81%, specificity of 78%, and accuracy of 91%.The result was present as a Receiver operating character (ROC) curve, which has an area under the curve (AUC) of 0.796 with 95% confidence intervals. CONCLUSION: This technique introduced a new automated detection algorithm to recognize non-perfusion lesions on FFA. This has potential to assist detecting and managing of ischemic retina and may be incorporated into automated grading diabetic retinopathy structures.

In vivo characterization of ischemic retina in diabetic retinopathy.

OBJECTIVE: The aim of this article is to characterize pathomorphologic changes within particular layers of fluorescein angiographically 'ischemic' compared to 'nonischemic' retina in patients with diabetic retinopathy. METHODS: Cross-sectional images of ischemic retinal areas were obtained using Heidelberg Spectralis optical coherence tomography (OCT). Presumed retinal ischemia was defined as focal hypofluorescence in early or early and late phase fluorescein angiography. Pathomorphologic changes on OCT were evaluated and the thickness of retinal layers measured and compared with nonischemic retina at corresponding topographic locations in a matched-pairs design based on 22 eyes (mean age 64 ± 14). RESULTS: In all eyes, based on spectral domain-OCT cross-section images, the retina layers in ischemic retinal areas could be segmented. Total retinal thickness was significantly increased in ischemic compared to nonischemic areas (381 ± 94 µm versus 323 ± 89 µm, P = 0.005). Middle retinal layers (inner nuclear layer, outer plexiform layer, and outer nuclear layer) were significantly thickened in retinal ischemic areas (215 ± 82 µm versus 168 ± 62 µm, P = 0.002). The inner retinal layers (retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer) showed a nonsignificant change (117 ± 53 µm versus 98 ± 30 µm), while the outer layers were slightly thinned (photoreceptors plus retinal pigment epithelium layer; 51 ± 9 µm versus 57 ± 8 µm, P = 0.02) in ischemic versus nonischemic retina. CONCLUSIONS: Ischemic diabetic retina seems to be thickened due to thickening of, in particular, middle retinal layers, which can be measured with high-resolution OCT.