α5β1 Integrin Promotes Anchoring and Integration of Transplanted Stem Cells to the Trabecular Meshwork in the Eye for Regeneration

Xiong, Siqi; Xu, Yi; Wang, Yiwen; Kumar, Ajay; Peters, Donna M.; Du, Yiqin

doi:10.1089/scd.2019.0254

Cited by 23 publications

(19 citation statements)

References 46 publications

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“…As the expression of myocilin can be induced by dexamethasone (Dex) in TM cells, we next characterized isolated primary human TM cells by their response to Dex [12]. As given in Fig.…”

Section: Tgf-β2 Enhances Myoc Y437h Mutation Induced Endoplasmic Retimentioning

confidence: 99%

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Yang

Abdulatef

Zhang³

et al. 2020

Int. J. Med. Sci.

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Objective: To identify the interaction between the MYOC Y437H mutation and TGF-β2 in a family with primary open-angle glaucoma (POAG). Methods: The MYOC Y437H mutation was identified in a family with POAG; the family was a fourth-generation family with 27 members, of which 6 members were affected. Analysis focused on the secreted myocilin protein and TGF-β2 found in the aqueous humor. Samples were taken both from normal controls and MYOC mutant carriers and cross-talk between MYOC Y437H and TGF-β2 were evaluated in the trabecular meshwork (TM) cells. Results: Aqueous humor secreted myocilin protein levels were reduced while TGF-β2 levels were increased in patients with the MYOC (c.1309T>C) mutation. This inverse relationship indicated that elevated TGF-β2 may be an important pathogenic mechanism in the progression of myocilin-related POAG. In TM cells expressing the MYOC Y437H mutant, exogenous TGF-β2 also significantly increased myocilin expression as well as the endoplasmic reticulum (ER) stress markers GRP94 and CHOP. This increase in TGF-β2 was also associated with increased cell death in cells carrying the MYOC Y437H mutation. Conclusion: These data collectively suggest that the mutual interaction between glaucomatous MYOC mutation and TGF-β2 contributed to the cell death of TM cells. This relationship also provides a new, therapeutic targets for the treatment of glaucoma.

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“…As the expression of myocilin can be induced by dexamethasone (Dex) in TM cells, we next characterized isolated primary human TM cells by their response to Dex [12]. As given in Fig.…”

Section: Tgf-β2 Enhances Myoc Y437h Mutation Induced Endoplasmic Retimentioning

confidence: 99%

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Yang

Abdulatef

Zhang³

et al. 2020

Int. J. Med. Sci.

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“…One of the mechanisms by which stem cells induce regeneration is differentiation into cells of desired lineage to compensate for deficient cells in the injured tissue. We previously reported that TMSCs ( Du et al, 2013 ; Xiong et al, 2020 ; Yun et al, 2018 ) and ADSCs ( Zhou et al, 2020 ) could differentiate into TM cells and express TM markers after homing to the TM tissues. However, the environment of the Tg-MyocY437H mouse TM where TMSCs stayed is different.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that TMSCs can regenerate the damaged TM tissue while corneal fibroblasts did not repair the damaged TM tissue ( Yun et al, 2018 ). Corneal fibroblasts did not express stem cell markers, such as NESTIN or OCT 4, which TMSCs were positive to and the fibroblasts did not home to and anchoring to the TM region after intracamerally injection ( Du et al, 2013 ; Xiong et al, 2020 ). All these suggest that TMSCs and corneal fibroblasts are distinctive in biological characteristics and behavior.…”

Section: Discussionmentioning

confidence: 99%

Stem cell transplantation rescued a primary open-angle glaucoma mouse model

Xiong

Kumar

Tian

et al. 2021

eLife

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Glaucoma is a leading cause of irreversible blindness. In this study, we investigated if transplanted stem cells are able to rescue a glaucoma mouse model with transgenic myocilin Y437H mutation and explored the possible mechanisms. Human trabecular meshwork stem cells (TMSCs) were intracamerally transplanted which reduced mouse intraocular pressure, increased outflow facility, protected the retinal ganglion cells and preserved their function. TMSC transplantation also significantly increased the TM cellularity, promoted myocilin secretion from TM cells into the aqueous humor to reduce endoplasmic reticulum stress, repaired the TM tissue with extracellular matrix modulation and ultrastructural restoration. Co-culturing TMSCs with myocilin mutant TM cells in vitro promoted TMSCs differentiating into phagocytic functional TM cells. RNA sequencing revealed that TMSCs had upregulated genes related to TM regeneration and neuroprotection. Our results uncovered therapeutic potential of TMSCs for curing glaucoma and elucidated possible mechanisms by which TMSCs achieve the treatment effect.

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“…In contrast to Piezo1 and TREK1 channels which are directly activated by pressure/stretch/indentation (89,90), the biophysical mechanism that activates TRPV4 channels in the presence of strain is not understood (81, 84, 91-93, 79, 80, 93, 95). It might involve β1 integrins, which bind the channel (5,30,87), are expressed in human and mouse TM (97,98), interact with ROCK (75), and contribute to IOP regulation and glaucoma (99,100). Interestingly, pretreatment with FAK or β1 integrin inhibitors suppressed sensitization of TRPV4 channels by mechanical stressors (Baratchi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Mechanically induced cytoskeletal remodeling in trabecular meshwork cells requires TRPV4 - Rho signaling interactions

Lakk¹,

Križaj

2020

Preprint

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Intraocular pressure (IOP) is dynamically regulated by the trabecular meshwork (TM), a mechanosensitive tissue that protects the eye from injury through dynamic regulation of aqueous humor outflow from the anterior chamber of the eye. IOP-dependent increases in TM stiffness and contractility drive open angle glaucoma but the mechanotransduction mechanisms that regulate these processes remain poorly understood. We used fluorescence imaging and biochemical analyses to investigate cytoskeletal and focal adhesion remodeling in human TM cells stimulated with cyclic strain. The cells showed enhanced F-actin polymerization, increased number and size of focal adhesions, and activation of the Rho-associated protein kinase (ROCK). Stretch-induced activation of the small GTPase RhoA, and tyrosine phosphorylations of focal adhesion proteins paxillin, focal adhesion kinase (FAK), vinculin and zyxin were time-dependently inhibited by HC-067047, an antagonist of transient receptor potential vanilloid 4 (TRPV4) channels, and the ROCK inhibitor Y-27632. TRPV4 and ROCK activation were required for zyxin translocation and increase in the number/size of focal adhesions in stretched cells. Y-27632 blocked actin polymerization without affecting calcium influx induced by membrane stretch and the TRPV4 agonist GSK1016790A. These results reveal that mechanical tuning of TM cells requires parallel activation of TRPV4, integrins and ROCK, with chronic stress leading to sustained remodeling of the cytoskeleton and focal complexes.

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α5β1 Integrin Promotes Anchoring and Integration of Transplanted Stem Cells to the Trabecular Meshwork in the Eye for Regeneration

Cited by 23 publications

References 46 publications

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Stem cell transplantation rescued a primary open-angle glaucoma mouse model

Mechanically induced cytoskeletal remodeling in trabecular meshwork cells requires TRPV4 - Rho signaling interactions

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