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Article: Tunneling nanotubes and actin cytoskeleton dynamics in glaucoma.

Keller, Kate E

2020 Volume 15, Issue 11, Page(s) 2031–2032

Language	English
Publishing date	2020-05-05
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.282254
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Article ; Online: Pathogenesis of glaucoma: Extracellular matrix dysfunction in the trabecular meshwork-A review.

Keller, Kate E / Peters, Donna M

Clinical & experimental ophthalmology

2022 Volume 50, Issue 2, Page(s) 163–182

Abstract: The trabecular meshwork regulates aqueous humour outflow from the anterior chamber of the eye. It does this by establishing a tunable outflow resistance, defined by the interplay between cells and their extracellular matrix (ECM) milieu, and the ... ...

Abstract	The trabecular meshwork regulates aqueous humour outflow from the anterior chamber of the eye. It does this by establishing a tunable outflow resistance, defined by the interplay between cells and their extracellular matrix (ECM) milieu, and the molecular interactions between ECM proteins. During normal tissue homeostasis, the ECM is remodelled and trabecular cell behaviour is modified, permitting increased aqueous fluid outflow to maintain intraocular pressure (IOP) within a relatively narrow physiological pressure. Dysfunction in the normal homeostatic process leads to increased outflow resistance and elevated IOP, which is a primary risk factor for glaucoma. This review delineates some of the changes in the ECM that lead to gross as well as some more subtle changes in the structure and function of the ECM, and their impact on trabecular cell behaviour. These changes are discussed in the context of outflow resistance and glaucoma.
MeSH term(s)	Aqueous Humor/metabolism ; Extracellular Matrix/metabolism ; Glaucoma/metabolism ; Humans ; Intraocular Pressure ; Trabecular Meshwork/metabolism
Language	English
Publishing date	2022-01-17
Publishing country	Australia
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2014008-3
ISSN	1442-9071 ; 1442-6404
ISSN (online)	1442-9071
ISSN	1442-6404
DOI	10.1111/ceo.14027
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Zs.A 1064: Show issues

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Article ; Online: Tunneling Nanotubes and the Eye: Intercellular Communication and Implications for Ocular Health and Disease.

Chinnery, Holly R / Keller, Kate E

BioMed research international

2020 Volume 2020, Page(s) 7246785

Abstract: Cellular communication is an essential process for the development and maintenance of all tissues including the eye. Recently, a new method of cellular communication has been described, which relies on formation of tubules, called tunneling nanotubes ( ... ...

Abstract	Cellular communication is an essential process for the development and maintenance of all tissues including the eye. Recently, a new method of cellular communication has been described, which relies on formation of tubules, called tunneling nanotubes (TNTs). These structures connect the cytoplasm of adjacent cells and allow the direct transport of cellular cargo between cells without the need for secretion into the extracellular milieu. TNTs may be an important mechanism for signaling between cells that reside long distances from each other or for cells in aqueous environments, where diffusion-based signaling is challenging. Given the wide range of cargoes transported, such as lysosomes, endosomes, mitochondria, viruses, and miRNAs, TNTs may play a role in normal homeostatic processes in the eye as well as function in ocular disease. This review will describe TNT cellular communication in ocular cell cultures and the mammalian eye
MeSH term(s)	Animals ; Biological Transport ; Biological Transport, Active ; Cell Communication ; Eye/metabolism ; Eye/pathology ; Eye Neoplasms/drug therapy ; Eye Neoplasms/metabolism ; Eye Neoplasms/pathology ; Humans ; Nanotubes
Language	English
Publishing date	2020-04-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2020/7246785
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Article: Effects of Netarsudil on Actin-Driven Cellular Functions in Normal and Glaucomatous Trabecular Meshwork Cells: A Live Imaging Study.

Keller, Kate E / Kopczynski, Casey

Journal of clinical medicine

2020 Volume 9, Issue 11

Abstract: The actin cytoskeleton of trabecular meshwork (TM) cells is a therapeutic target for lowering intraocular pressure (IOP) in glaucoma patients. Netarsudil (the active ingredient in ... ...

Abstract	The actin cytoskeleton of trabecular meshwork (TM) cells is a therapeutic target for lowering intraocular pressure (IOP) in glaucoma patients. Netarsudil (the active ingredient in Rhopressa
Language	English
Publishing date	2020-10-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm9113524
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Article: The Effects of Mechanical Stretch on Integrins and Filopodial-Associated Proteins in Normal and Glaucomatous Trabecular Meshwork Cells.

Yang, Yong-Feng / Sun, Ying Ying / Peters, Donna M / Keller, Kate E

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 886706

Abstract: The trabecular meshwork (TM) is the tissue responsible for regulating aqueous humor fluid egress from the anterior eye. If drainage is impaired, intraocular pressure (IOP) becomes elevated, which is a primary risk factor for primary open angle glaucoma. ... ...

Abstract	The trabecular meshwork (TM) is the tissue responsible for regulating aqueous humor fluid egress from the anterior eye. If drainage is impaired, intraocular pressure (IOP) becomes elevated, which is a primary risk factor for primary open angle glaucoma. TM cells sense elevated IOP via changes in their biomechanical environment. Filopodia cellular protrusions and integrin transmembrane proteins may play roles in detecting IOP elevation, yet this has not been studied in detail in the TM. Here, we investigate integrins and filopodial proteins, such as myosin-X (Myo10), in response to mechanical stretch, an
Language	English
Publishing date	2022-04-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.886706
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Article: Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model.

Lozano, Diana C / Yang, Yong-Feng / Cepurna, William O / Smoody, Barbara F / Ing, Eliesa / Morrison, John C / Keller, Kate E

bioRxiv : the preprint server for biology

2024

Abstract: Purpose: The rat Controlled Elevation of Intraocular pressure (CEI) model allows study of : Methods: Male and female rats (N=35) were subject to CEI for 8-hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5x IOP (CEI-50). ...

Abstract	Purpose: The rat Controlled Elevation of Intraocular pressure (CEI) model allows study of Methods: Male and female rats (N=35) were subject to CEI for 8-hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5x IOP (CEI-50). Naïve animals, receiving no anesthesia or surgical interventions, served as controls. Immediately after CEI, TM and ONH tissues were dissected, RNA isolated, and samples were analyzed with a Nanostring panel containing 770 genes. Post-processing, raw count data were uploaded to Rosalind® for differential gene expression analyses. Results: For the TM, 45 IOP-related genes were significant in the "CEI-50 vs. CEI-20" and "CEI-50 vs. naïve" comparisons, with 15 genes common to both comparisons. Bioinformatics analysis identified Notch and TGFβ pathways to be the most up- and down-regulated KEGG pathways, respectively. For ONH, 22 significantly regulated genes were identified in the "CEI-50 vs. naïve" comparison. Pathway analysis identified 'defense response' and 'immune response' as two significantly upregulated biological process pathways. Conclusions: This study demonstrates the ability to assay IOP-responsive genes in both TM and ONH tissues simultaneously. In the TM, downregulation of TGFβ pathway genes suggest that TM responses may prevent TGFβ-induced extracellular matrix synthesis. For ONH, the initial response to elevated IOP may be protective, with astrocytes playing a key role in these gene responses.
Language	English
Publishing date	2024-02-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.11.579818
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Article ; Online: Digital spatial profiling of segmental outflow regions in trabecular meshwork reveals a role for ADAM15.

Faralli, Jennifer A / Filla, Mark S / Yang, Yong-Feng / Sun, Ying Ying / Johns, Kassidy / Keller, Kate E / Peters, Donna M

PloS one

2024 Volume 19, Issue 2, Page(s) e0298802

Abstract: In this study we used a spatial transcriptomics approach to identify genes specifically associated with either high or low outflow regions in the trabecular meshwork (TM) that could potentially affect aqueous humor outflow in vivo. High and low outflow ... ...

Abstract	In this study we used a spatial transcriptomics approach to identify genes specifically associated with either high or low outflow regions in the trabecular meshwork (TM) that could potentially affect aqueous humor outflow in vivo. High and low outflow regions were identified and isolated from organ cultured human anterior segments perfused with fluorescently-labeled 200 nm FluoSpheres. The NanoString GeoMx Digital Spatial Profiler (DSP) platform was then used to identified genes in the paraffin embedded tissue sections from within those regions. These transcriptome analyses revealed that 16 genes were statistically upregulated in high outflow regions and 57 genes were statistically downregulated in high outflow regions when compared to low outflow regions. Gene ontology enrichment analysis indicated that the top three biological categories of these differentially expressed genes were ECM/cell adhesion, signal transduction, and transcription. The ECM/cell adhesion genes that showed the largest differential expression (Log2FC ±1.5) were ADAM15, BGN, LDB3, and CRKL. ADAM15, which is a metalloproteinase that can bind integrins, was upregulated in high outflow regions, while the proteoglycan BGN and two genes associated with integrin signaling (LDB3, and CRKL) were downregulated. Immunolabeling studies supported the differential expression of ADAM15 and showed that it was specifically upregulated in high outflow regions along the inner wall of Schlemm's canal and in the juxtacanalicular (JCT) region of the TM. In addition to these genes, the studies showed that genes for decorin, a small leucine-rich proteoglycan, and the α8 integrin subunit were enriched in high outflow regions. These studies identify several novel genes that could be involved in segmental outflow, thus demonstrating that digital spatial profiling could be a useful approach for understanding segmental flow through the TM. Furthermore, this study suggests that changes in the expression of genes involved in regulating the activity and/or organization of the ECM and integrins in the TM are likely to be key players in segmental outflow.
MeSH term(s)	Humans ; Trabecular Meshwork/metabolism ; Aqueous Humor/metabolism ; Sclera ; Proteoglycans/metabolism ; Integrins/genetics ; Integrins/metabolism ; Intraocular Pressure ; Membrane Proteins/metabolism ; ADAM Proteins/metabolism
Chemical Substances	Proteoglycans ; Integrins ; ADAM15 protein, human (EC 3.4.24.-) ; Membrane Proteins ; ADAM Proteins (EC 3.4.24.-)
Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0298802
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Article ; Online: A method describing the microdissection of trabecular meshwork tissue from Brown Norway rat eyes.

Ing, Eliesa / Lozano, Diana C / Cepurna, William O / Chan, Fountane / Yang, Yong-Feng / Morrison, John C / Keller, Kate E

Experimental eye research

2023 Volume 228, Page(s) 109367

Abstract: Glaucoma is often associated with elevated intraocular pressure (IOP), generally due to obstruction of aqueous humor outflow within the trabecular meshwork (TM). Despite many decades of research, the molecular cause of this obstruction remains elusive. ... ...

Abstract	Glaucoma is often associated with elevated intraocular pressure (IOP), generally due to obstruction of aqueous humor outflow within the trabecular meshwork (TM). Despite many decades of research, the molecular cause of this obstruction remains elusive. To study IOP regulation, several in vitro models, such as perfusion of anterior segments or mechanical stretching of TM cells, have identified several IOP-responsive genes and proteins. While these studies have proved informative, they do not fully recapitulate the in vivo environment where IOP is subject to additional factors, such as circadian rhythms. Thus, rodent animal models are now commonly used to study IOP-responsive genes in vivo. Several single-cell RNAseq studies have been performed where angle tissue, containing cornea, iris, ciliary body tissue in addition to TM, is dissected. However, it is advantageous to physically separate TM from other tissues because the ratio of TM cells is relatively low compared to the other cell types. In this report, we describe a new technique for rat TM microdissection. Evaluating tissue post-dissection by histology and immunostaining clearly shows successful removal of the TM. In addition, TaqMan PCR primers targeting biomarkers of trabecular meshwork (Myoc, Mgp, Chi3l1) or ciliary body (Myh11, Des) genes showed little contamination of TM tissue by the ciliary body. Finally, pitfalls encountered during TM microdissection are discussed to enable others to successfully perform this microsurgical technique in the rat eye.
MeSH term(s)	Rats ; Animals ; Trabecular Meshwork/metabolism ; Microdissection ; Aqueous Humor/metabolism ; Glaucoma/metabolism ; Iris ; Intraocular Pressure
Language	English
Publishing date	2023-02-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2022.109367
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Article ; Online: Myosin-X Silencing in the Trabecular Meshwork Suggests a Role for Tunneling Nanotubes in Outflow Regulation.

Sun, Ying Ying / Yang, Yong-Feng / Keller, Kate E

Investigative ophthalmology & visual science

2019 Volume 60, Issue 2, Page(s) 843–851

Abstract: Purpose: The actin cytoskeleton plays a key role in outflow regulation through the trabecular meshwork (TM). Although actin stress fibers are a target of glaucoma therapies, the role of other actin cellular structures is unclear. Myosin-X (Myo10) is an ... ...

Abstract	Purpose: The actin cytoskeleton plays a key role in outflow regulation through the trabecular meshwork (TM). Although actin stress fibers are a target of glaucoma therapies, the role of other actin cellular structures is unclear. Myosin-X (Myo10) is an actin-binding protein that is involved in tunneling nanotube (TNT) and filopodia formation. Here, we inhibited Myo10 pharmacologically or by gene silencing to investigate the role of filopodia/TNTs in the TM. Methods: Short hairpin RNA interference (RNAi) silencing lentivirus targeting myosin-X (shMyo10) was generated. Human anterior segments were perfused with shMyo10 or CK-666, an Arp2/3 inhibitor. Confocal microscopy investigated the colocalization of Myo10 with matrix metalloproteinase (MMPs). Western immunoblotting investigated the protein levels of MMPs and extracellular matrix (ECM) proteins. MMP activity and phagocytosis assays were performed. Results: CK-666 and shMyo10-silencing lentivirus caused a significant reduction in outflow rates in anterior segment perfusion culture, an ex vivo method to study intraocular pressure regulation. In human TM cells, Myo10 colocalized with MMP2, MMP14, and cortactin in podosome-like structures, which function as regions of focal ECM degradation. Furthermore, MMP activity, thrombospondin-1 and SPARC protein levels were significantly reduced in the media of CK-666-treated and shMyo10-silenced TM cells. However, neither Myo10 silencing or CK-666 treatment significantly affected phagocytic uptake. Conclusions: Inhibiting filopodia/TNTs caused opposite effects on outflow compared with inhibiting stress fibers. Moreover, Myo10 may also play a role in focal ECM degradation in TM cells. Our results provide additional insight into the function of actin supramolecular assemblies and actin-binding proteins in outflow regulation.
MeSH term(s)	Aged ; Aged, 80 and over ; Aqueous Humor/physiology ; Blotting, Western ; Extracellular Matrix Proteins/metabolism ; Female ; Fluorescent Antibody Technique, Indirect ; Gene Silencing ; Humans ; Indoles/pharmacology ; Lentivirus/genetics ; Male ; Matrix Metalloproteinases/metabolism ; Microscopy, Confocal ; Microvessels/physiology ; Middle Aged ; Myosins/physiology ; Nanotubes ; Phagocytosis ; Pseudopodia/drug effects ; Pseudopodia/metabolism ; RNA Interference/physiology ; Real-Time Polymerase Chain Reaction ; Trabecular Meshwork/metabolism
Chemical Substances	CK-0944666 ; Extracellular Matrix Proteins ; Indoles ; MYO10 protein, human ; Matrix Metalloproteinases (EC 3.4.24.-) ; Myosins (EC 3.6.4.1)
Language	English
Publishing date	2019-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.18-26055
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Article ; Online: Phenotypic and Functional Alterations in Tunneling Nanotubes Formed by Glaucomatous Trabecular Meshwork Cells.

Sun, Ying Ying / Bradley, John M / Keller, Kate E

Investigative ophthalmology & visual science

2019 Volume 60, Issue 14, Page(s) 4583–4595

Abstract: Purpose: Trabecular meshwork (TM) cells detect and coordinate responses to intraocular pressure (IOP) in the eye. TM cells become dysfunctional in glaucoma where IOP is often elevated. Recently, we showed that normal TM (NTM) cells communicate by ... ...

Abstract	Purpose: Trabecular meshwork (TM) cells detect and coordinate responses to intraocular pressure (IOP) in the eye. TM cells become dysfunctional in glaucoma where IOP is often elevated. Recently, we showed that normal TM (NTM) cells communicate by forming tubular connections called tunneling nanotubes (TNTs). Here, we investigated TNTs in glaucomatous TM (GTM) cells. Methods: Primary GTM and NTM cells were established from cadaver eyes. Transfer of Vybrant DiO and DiD-labeled vesicles via TNT connections was measured. Imaris software measured the number and length of cell protrusions from immunofluorescent confocal images. Live-cell imaging of the actin cytoskeleton was performed. The distribution of myosin-X, a regulator of TNTs/filopodia, was investigated in TM cells and tissue. Results: GTM cells contained significantly more transferred fluorescent vesicles than NTM cells (49.6% vs. 35%). Although NTM cells had more protrusions at the cell surface than GTM cells (7.61 vs. 4.65 protrusions/cell), GTM protrusions were significantly longer (12.1 μm vs. 9.76 μm). Live-cell imaging demonstrated that the GTM actin cytoskeleton was less dynamic, and vesicle transfer between cells was significantly slower than NTM cells. Furthermore, rearrangement of the actin cortex adjacent to the TNT may influence TNT formation. Myosin-X immunostaining was punctate and disorganized in GTM cells and tissue compared to age-matched NTM controls. Conclusions: Together, our data demonstrate that GTM cells have phenotypic and functional differences in their TNTs. Significantly slower vesicle transfer via TNTs in GTM cells may delay the timely propagation of cellular signals when pressures become elevated in glaucoma.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Blotting, Western ; Cell Size ; Cells, Cultured ; Cellular Senescence/physiology ; Densitometry ; Glaucoma, Open-Angle/metabolism ; Glaucoma, Open-Angle/pathology ; Humans ; Microscopy, Confocal ; Myosins/metabolism ; Nanotubes ; Phagocytosis/physiology ; Phenotype ; Pseudopodia/metabolism ; Signal Transduction/physiology ; Trabecular Meshwork/metabolism ; Trabecular Meshwork/pathology
Chemical Substances	MYO10 protein, human ; Myosins (EC 3.6.4.1)
Language	English
Publishing date	2019-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.19-28084
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