Zonule-Associated Gene Variants in Isolated Ectopia Lentis and Glaucoma

Longxiang, Huang; Xu, Tingting; Gan, Jiahe; Mao, Yukai; Zhao, Lian; Jiao, Xiaodong; Fan, Mengjie; Wang, Tingting; Zhang, Daren; Xu, Meng; Chen, Jinyuan; Hejtmancik, J. Fielding; Liu, Xuyang

doi:10.1097/ijg.0000000000002209

Cited by 1 publication

(1 citation statement)

References 55 publications

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“…Another recent study found an increased expression of LTBP1 in the keratotomy wounds of mouse corneas [ 67 ]. LTBP2 dysregulation has been linked to eye diseases in numerous studies, including glaucoma [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. Two studies reported LTBP1 and LTBP2 upregulation in the anterior segment of human tissues with pseudoexfoliation syndrome [ 78 , 79 ].…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

Nicholas,

Basu,

Mandal

et al. 2024

IJMS

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Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I2; prevention groups; (4) S1P/β1; and (5) I2/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis.

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