Effect of SOX2 Repression on Corneal Endothelial Cells

Hwang, Jiyoung; Yi, Ho Chul; Shin, Young Joo

doi:10.3390/ijms21124397

Cited by 5 publications

(8 citation statements)

References 44 publications

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“…SOX2 plays a critical role in eye development, participating in differentiation during the development of the AS. 43,44 It closely interacts with PAX6 during early lens development, and SOX2 expression level has been detected in the developing lens vesicle of human embryos. 26,43 This transcription factor also plays a crucial role in NCC formation that is essential in AS development.…”

Section: Discussionmentioning

confidence: 99%

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

et al. 2022

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Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido‐lenticulo‐corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro‐anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.

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Section: Discussionmentioning

confidence: 99%

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

et al. 2022

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“…RMST works this way in neurons, where it promotes neurogenic differentiation of stem cells by interacting with the transcription factor SOX2 to co-regulate a large pool of downstream genes that are essential for neurogenesis ( Ng et al, 2013 ). Whether this is the case in ECs is unclear, as little is known about the functional roles of SOX2 in ECs, although one study has shown that SOX2 knockdown attenuates survival, proliferation, and migration in corneal ECs due to downregulation of cyclin D1 and CDK1 and upregulation of CDKN2A, a cell cycle inhibitor ( Hwang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNA Rhabdomyosarcoma 2-Associated Transcript Regulates Angiogenesis in Endothelial Cells

2021

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Background: Long non-coding RNAs (lncRNAs) are non-coding RNAs that have more than 200 nucleotides. They have recently emerged as important regulators of angiogenesis. To identify novel lncRNAs that may be involved in the regulation of angiogenesis, we detected the mRNA of 84 lncRNAs in human umbilical vein endothelial cells (HUVECs) exposed to hypoxia for 24h. One of these, rhabdomyosarcoma 2-associated transcript (RMST), is significantly upregulated by hypoxia. Little is known about the presence and roles of RMST in EC function.Objective: The main objective of the study was to investigate the regulation of RMST in ECs and to determine its role in EC survival, proliferation, migration, and differentiation.Methods: Using qPCR, basal mRNA levels of 10 RMST isoforms in HUVECs were measured. Levels were then measured in response to 24h of hypoxia, 7days of differentiation in a co-culture assay, and exposure to four different angiogenesis factors. Functional roles of RMST in EC survival, migration, and differentiation were quantified by using a loss-of-function approach (transfection with single-stranded antisense LNA GapmeRs). EC survival was measured using cell counts and crystal violet assays. Cell migration and differentiation were measured using scratch wound healing and Matrigel® differentiation assays, respectively.Results: Five RMST isoforms (RMST-202, -203, -204, -206, and -207) were detected in HUVECs and human microvascular endothelial cells (HMEC-1s). Other types of vascular cells, including human aortic valve interstitial cells and human aortic smooth muscle cells, did not display this expression profile. RMST was significantly upregulated in response to 24h of hypoxia and in response to 7days of HUVEC co-culture with human lung fibroblasts. RMST was significantly downregulated by angiopoietin-2 (Ang-2), but not by VEGF, FGF-2, or angiopoietin-1 (Ang-1). Selective knockdown of RMST demonstrated that it promotes EC survival in response to serum deprivation. It is also required for VEGF- and Ang-1-induced EC survival and migration, but not for differentiation.Conclusion: We conclude that RMST is expressed in human ECs and that this expression is upregulated in response to hypoxia and during differentiation into capillary-like structures. We also conclude that RMST plays important roles in EC survival and migration.

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Section: Methodsmentioning

confidence: 99%

“…Cells (1 × 10 4 ) per well were seeded in a 96-well plate and treated with miRNA for 48–72 h. Cell viability was evaluated using a cell counting kit-8 (CCK-8; Dojindo, Kumamoto) [ 73 ]. After incubation with CCK-8 solution for 1–2 h, a Synergy HTX (BioTEK, Winooski, VT) multi-mode reader was used for evaluating cell viability by measuring optical density (OD) at 450 nm [ 73 ]. A bromodeoxyuridine (BrdU) incorporation assay kit (Roche Diagnostics, GmbH, Mannheim, Germany) was employed for evaluating cell proliferation rate according to manufacturer’s protocol [ 72 ].…”

Section: Methodsmentioning

confidence: 99%

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miR-30c-1 encourages human corneal endothelial cells to regenerate through ameliorating senescence

Younghwan

Hwang

Shin

2021

Aging

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In the present study, we studied the role of microRNA-30c-1 (miR-30c-1) on transforming growth factor beta1 (TGF-β1)-induced senescence of hCECs. hCECs were transfected by miR-30c-1 and treated with TGF-β1 to assess the inhibitory effect of miR-30c-1 on TGF-β1-induced senescence. Cell viability and proliferation rate in miR-30c-1-transfected cells was elevated compared with control. Cell cycle analysis revealed that cell abundance in S phase was elevated in miR-30c-1-treated cells compared with control. TGF-β1 increased the senescence of hCECs; however, this was ameliorated by miR-30c-1. TGF-β1 increased the size of hCECs, the ratio of senescence-associated beta-galactosidase-stained cells, secretion of senescence-associated secretory phenotype factors, the oxidative stress, and arrested the cell cycle, all of which were ameliorated by miR-30c-1 treatment. miR-30c-1 also suppressed a TGF-β1-induced depolarization of mitochondrial membrane potential and a TGF-β1 stimulated increase in levels of cleaved poly (ADP-ribose) polymerase (PARP), cleaved caspase 3, and microtubule-associated proteins 1A/1B light chain 3B II. In conclusion, miR-30c-1 promoted the proliferation of hCECs through ameliorating the TGF- β1-induced senescence of hCECs and reducing cell death of hCECs. Thus, miR-30c-1 may be a therapeutic target for hCECs regeneration.

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Effect of SOX2 Repression on Corneal Endothelial Cells

Cited by 5 publications

References 44 publications

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

Long Non-coding RNA Rhabdomyosarcoma 2-Associated Transcript Regulates Angiogenesis in Endothelial Cells

miR-30c-1 encourages human corneal endothelial cells to regenerate through ameliorating senescence

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