ROCK Inhibitor Y-27632 Promotes Human Retinal Pigment Epithelium Survival by Altering Cellular Biomechanical Properties

Ni, Yanbo; Qin, Yufeng; Fang, Zongjuan; Zhang, Z

doi:10.2174/1566524018666180316150936

Cited by 7 publications

(7 citation statements)

References 49 publications

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“…For example, intravitreally injected fasudil reduced retinal hypoxia and RPE barrier breakdown in Goto Kakizaki type 2 diabetic rats [69]. Ni et al investigating the effect of a ROCK inhibitor (Y-27632) on ARPE19 cells, observed increased proliferation and reduced apoptosis of RPE cells [70]. In our study, ARPE19 cells appeared unaffected by treatment with free and released fasudil.…”

Section: Discussionsupporting

confidence: 47%

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

et al. 2020

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Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to supply outflow tissues with the ROCK inhibitor fasudil over a prolonged time. Fasudil-loaded microspheres were prepared by double emulsion solvent evaporation technique. The chemical integrity of released fasudil was confirmed by mass spectrometry. The biological activity was measured in cell-based assays using trabecular meshwork cells (TM cells), Schlemm’s canal cells (SC cells), fibroblasts and adult retinal pigment epithelium cells (ARPE-19). Cellular response to fasudil after its diffusion through vitreous humor was investigated by electric cell-substrate impedance sensing. Microspheres ranged in size from 3 to 67 µm. The release of fasudil from microspheres was controllable and sustained for up to 45 days. Released fasudil reduced actin stress fibers in TM cells, SC cells and fibroblasts. Decreased collagen gel contraction provoked by fasudil was detected in TM cells (~2.4-fold), SC cells (~1.4-fold) and fibroblasts (~1.3-fold). In addition, fasudil readily diffused through vitreous humor reaching its target compartment and eliciting effects on TM cells. No negative effects on ARPE-19 cells were observed. Since fasudil readily diffuses through the vitreous humor, we suggest that an intravitreal drug depot of ROCK inhibitors could significantly improve current glaucoma therapy particularly for patients with comorbid retinal diseases.

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Section: Discussionsupporting

confidence: 47%

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

et al. 2020

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“…We found that the CR cell’s cytoskeleton appeared elongated with no difference in cell membrane height nor any immediate difference in the appearance of goblet cells or cilia from cross-sectional images. Previously, ROCK inhibitor has been shown to alter the biochemical properties of a cell by influencing the reorganization of cytoskeletal microfilaments and microtubules in retinal pigment epithelium ( 27 ). Future detailed studies of the cell cytoskeleton are warranted in CR cells before their use to answer research questions where cytoskeletal arrangements may be critical.…”

Section: Discussionmentioning

confidence: 99%

Conditionally reprogrammed asthmatic bronchial epithelial cells express lower FOXJ1 at terminal differentiation and lower IFNs following RV-A1 infection

Veerati

Nichol

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et al. 2022

American Journal of Physiology-Lung Cellular and Molecular Phys

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Primary bronchial epithelial cells (pBECs) obtained from donors have limited proliferation capacity. Recently, conditional reprogramming (CR) technique has overcome this and has provided the potential for extended passaging and subsequent differentiation of cells at air-liquid interface (ALI). However, there has been no donor-specific comparison of cell morphology, baseline gene expression, barrier function and anti-viral responses compared to their 'parent' pBECs, especially cells obtained from asthma donors. We, therefore, collected and differentiated pBECs at ALI from mild asthma donors (n=6) for the parent group. The same cells were conditionally reprogrammed and later differentiated at ALI. Barrier function was measured during the differentiation phase. Morphology and baseline gene expression were compared at terminal differentiation. Viral replication kinetics and anti-viral responses were assessed following RV infection over 96 hours. Barrier function during the differentiation phase and cell structural morphology at terminal differentiation appear similar in both parent and CR groups, however, there were elongated cell structures superficial to basal cells and significantly lower FOXJ1 expression in CR group. Anti-viral responses were also lower in CR group compared to parent asthma group following RV infection. The CR technique is a beneficial tool to proliferate pBECs over extended passages. Considering lower FOXJ1 expression, viral replication kinetics and anti-viral responses, a cautious approach should be taken while choosing CR cells for experiments. In addition, as lab-to-lab cell culture techniques vary, the most appropriate technique must be utilized to best match individual cell functions and morphologies to address specific research questions and experimental reproducibility across the labs.

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“…The PDMS-based culture device, which had a 0.2-mm curvature radius, was able to provide appropriate physical conditions for the formation and harvesting of RPE strips in a straightforward manner. The addition of Y-27632 generally suppresses contractility 15 and elongates the shape of human RPE 16 . In this study, the microgroove appeared to define the direction of cell elongation, resulting in shrinkage of the strip at a higher concentration of Y-27632, as a synergistic effect between physical and pharmacological conditions.…”

Section: Discussionmentioning

confidence: 95%

Human iPS cell derived RPE strips for secure delivery of graft cells at a target place with minimal surgical invasion

Nishida

Tanaka

et al. 2021

Sci Rep

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Several clinical studies have been conducted into the practicality and safety of regenerative therapy using hESC/iPSC-retinal pigment epithelium (RPE) as a treatment for the diseases including age-related macular degeneration. These studies used either suspensions of RPE cells or an RPE cell sheet. The cells can be injected using a minimally invasive procedure but the delivery of an intended number of cells at an exact target location is difficult; cell sheets take a longer time to prepare, and the surgical procedure is invasive but can be placed at the target area. In the research reported here, we combined the advantages of the two approaches by producing a quickly formed hiPSC-RPE strip in as short as 2 days. The strip readily expanded into a monolayer sheet on the plate, and after transplantation in nude rats, it showed a potency to partly expand with the correct apical/basal polarity in vivo, although limited in expansion area in the presence of healthy host RPE. The strip could be injected into a target area in animal eyes using a 24G canula tip.

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ROCK Inhibitor Y-27632 Promotes Human Retinal Pigment Epithelium Survival by Altering Cellular Biomechanical Properties

Cited by 7 publications

References 49 publications

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

Conditionally reprogrammed asthmatic bronchial epithelial cells express lower FOXJ1 at terminal differentiation and lower IFNs following RV-A1 infection

Human iPS cell derived RPE strips for secure delivery of graft cells at a target place with minimal surgical invasion

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