Regulation of Limbal Epithelial Stem Cells: Importance of the Niche

Robertson, Sarah; Roberts, JoAnn S.; Deng, Sophie X.

doi:10.3390/ijms222111975

Cited by 19 publications

(11 citation statements)

References 147 publications

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“…Several studies in recent years have highlighted the importance of maintaining the limbal niche for the proper functioning of LESCs. 36,37 Previous studies reported an increase in lipid content in diabetic corneas, with the most significant increase in sphingosine, whose phosphorylation product affected wound healing. 38 The current study concluded that LDL and TC correlated with stem cell parameters, suggesting that lipid metabolism dysfunction within the limbal niche potentially influenced LESCs, as previously reported in other stem cell microenvironments.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study

Chen

Wang

Guo

et al. 2023

Cornea

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Purpose: This study aimed to investigate corneal limbus changes in patients with type 2 diabetes mellitus (DM) using in vivo confocal microscopy (IVCM) and explore the correlation between their ocular manifestations and systemic status. Methods: Fifty-five patients with type 2 DM and 20 age-matched controls were included. The following IVCM parameters were compared between the 2 groups: palisades of Vogt (POV), corneal epithelial thickness (CET), basal cell density (BCD), subbasal nerve plexus, and dendritic cell density. All subjects underwent blood and urine sampling for laboratory analysis, including fasting blood glucose, glycated hemoglobin, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein, urinary albumin-to-creatinine ratio, urine albumin, and urine creatinine. The correlations between IVCM parameters and blood biomarkers were detected. Receiver operating characteristic curve was used for selecting the cutoff value of risk factors for corneal stem cell injury in patients with DM. Results: Compared with controls, patients with DM displayed a significant reduction of POV (superior region, P = 0.033; inferior region, P = 0.003; nasal region, P < 0.001; temporal region, P < 0.001), central CET (44.8 ± 3.6 μm vs. 51.9 ± 3.6 μm, P < 0.001), central corneal BCD (7415.5 ± 563.2 cells/mm2 vs. 9177.9 ± 977.8 cells/mm2, P < 0.001), and peripheral corneal BCD (6181.3 ± 416.5 cells/mm2 vs. 8576.3 ± 933.2 cells/mm2, P < 0.001). Dendritic cell density (41.0 ± 33.7 cells/mm2 vs. 24.6 ± 7.8 cells/mm2, P = 0.001) was significantly higher in the DM group. The following weak correlations were shown between IVCM parameters and blood biomarkers: central corneal BCD was negatively correlated with DM duration (r = −0.3, P = 0.024), TC (r = −0.36, P = 0.007), and LDL (r = −0.39, P = 0.004). The presence of POV in the superior region was negatively correlated with TC (r = −0.34, P = 0.011) and LDL (r = −0.31, P = 0.022). Cutoff values of 1.215 mmol/L for HDL, 1.59 mmol/L for TG, or 4.75 mmol/L for TC were established to distinguish patients with a high risk from a low risk for stem cell damage. Conclusions: Patients with type 2 DM displayed a lower positive rate of typical POV and a decrease in BCD, CET, and subbasal nerve density. The most relevant indicators for stem cell phenotypes were DM duration, TC, and LDL. Lipid status in diabetic patients could be a predictor of risk for developing corneal limbal stem cell deficiency. Further studies with larger sample sizes or basic research are needed to verify the results.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study

Chen

Wang

Guo

et al. 2023

Cornea

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“…The normal limbus and LSCs act as a barrier to prevent conjunctival epithelial cells from invading the cornea [ 22 ]. LSCs are quiescent stem cells that can be activated to divide symmetrically and asymmetrically, producing proliferative progenitor cells that produce mature corneal epithelial cells [ 23 ]. Our results demonstrated that the addition of exogenous MLN4924 in vivo and in vitro could effectively maintain the stemness of LSCs and promote LSC proliferation.…”

Section: Discussionmentioning

confidence: 99%

MLN4924 Promotes Self-Renewal of Limbal Stem Cells and Ocular Surface Restoration

Shen

et al. 2023

JPM

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Objective: To study the role of MLN4924 in corneal stem cell maintenance and corneal injury repair. Methods: In cell experiments, the Sprague–Dawley (SD) rat corneal epithelial cells were co-cultured with mitomycin C-inactivated mouse feeder cells in a supplemental hormonal epithelial medium (SHEM) with or without MLN4924. Cells were photographed using an optical microscope. Furthermore, we performed crystal violet, polymerase chain reaction (PCR), and immunofluorescence staining on limbal stem cells (LSCs). In animal experiments, we scraped the corneal epithelium with a central corneal diameter of 4 mm in SD rats. The area of the corneal epithelial defect was calculated by fluorescein sodium staining. Results: LSCs in the MLN4924 group had significantly proliferated. The MLN4924 treatment evidently enhanced the clone formation rate and clone area of LSCs. The expression levels of Ki67, p63, ABCG2, Bmi1, and C/EBPδ increased in LSCs after MLN4924 treatment, whereas the expression of K12 decreased. At 12 and 24 h after scraping, the corneal epithelium recovery rate in the eyes of the MLN4924-treated rats was accelerated. Conclusions: MLN4924 can maintain stemness, reduce differentiation, promote the proliferative capacity of rat LSCs, and accelerate corneal epithelial wound healing in SD rats.

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“…Molecular regulation of LSCs is another approach to supplement soluble factors that sustain the self-renewal of LSCs both in vitro and in vivo. Several signaling pathways such as Wnt, Notch, BMP, Shh, YAP, and TGFb play critical roles in the maintenance and differentiation of LSCs [40][41][42][43][44]. Activation of Wnt signaling and modulation of Notch signaling are shown to impact the LSC proliferation and differentiation in culture, which opens a new approach in enhancing LSC expansion efficiency and survival of LSCs upon chemical injury in culture [45].…”

Section: Restoration Of Limbal Stem Cell Nichementioning

confidence: 99%

Limbal stem cell therapy

Bonnet,

Gonzalez,

Deng

2024

Current Opinion in Ophthalmology

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Purpose of review To highlight the progress and future direction of limbal stem cell (LSC) therapies for the treatment of limbal stem cell deficiency (LSCD). Recent findings Direct LSC transplantation have demonstrated good long-term outcomes. Cultivated limbal epithelial transplantation (CLET) has been an alternative to treat severe to total LSCD aiming to improve the safety and efficacy of the LSC transplant. A prospective early-stage uncontrolled clinical trial shows the feasibility and safety of CLET manufactured under xenobiotic free conditions. Other cell sources for repopulating of the corneal epithelium such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells are being investigated. The first clinical trials of using MSCs showed short-term results, but long-term efficacy seems to be disappointing. A better understanding of the niche function and regulation of LSC survival and proliferation will lead to the development of medical therapies to rejuvenate the residual LSCs found in a majority of eyes with LSCD in vivo. Prior efforts have been largely focused on improving LSC transplantation. Additional effort should be placed on improving the accuracy of diagnosis and staging of LSCD, and implementing standardized outcome measures which enable comparison of efficacy of different LSCD treatments for different severity of LSCD. The choice of LSCD treatment will be customized based on the severity of LSCD in the future. Summary New approaches for managing different stages of LSCD are being developed. This concise review summarizes the progresses in LSC therapies for LSCD, underlying mechanisms, limitations, and future areas of development.

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Regulation of Limbal Epithelial Stem Cells: Importance of the Niche

Cited by 19 publications

References 147 publications

Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study

Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study

MLN4924 Promotes Self-Renewal of Limbal Stem Cells and Ocular Surface Restoration

Limbal stem cell therapy

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