scholarly journals Loss of retinal ganglion cells in a new genetic mouse model for primary open‐angle glaucoma

2019 ◽  
Vol 23 (8) ◽  
pp. 5497-5507 ◽  
Author(s):  
Sabrina Reinehr ◽  
Dennis Koch ◽  
Maximilian Weiss ◽  
Franziska Froemel ◽  
Christina Voss ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinal Ganglion Cells ◽  
Primary Open Angle Glaucoma ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Retinal Ganglion ◽  
Open Angle ◽  
Genetic Mouse Model

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Siqi Xiong ◽  
Ajay Kumar ◽  
Shenghe Tian ◽  
Eman E Taher ◽  
Enzhi Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Retinal Ganglion Cells ◽  
Primary Open Angle Glaucoma ◽  
Therapeutic Potential ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Retinal Ganglion ◽  
Upregulated Genes

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.

scholarly journals Genomic Locus Modulating Corneal Thickness in the Mouse Identifies POU6F2 as a Potential Risk of Developing Glaucoma

2017 ◽  
Author(s):  
Rebecca King ◽  
Felix L. Struebing ◽  
Ying Li ◽  
Jiaxing Wang ◽  
Allison Ashley Koch ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Retinal Ganglion Cells ◽  
Central Corneal Thickness ◽  
Primary Open Angle Glaucoma ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Corneal Thickness ◽  
Retinal Ganglion ◽  
Open Angle

AbstractPurpose: Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG.Methods: The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to identify quantitative trait loci (QTLs) modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human primary open-angle glaucoma (POGA) genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.Results: This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs.Conclusions: Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.Authors SummaryGlaucoma is a complex group of diseases with several known causal mutations and many known risk factors. One well-known risk factor for developing primary open angle glaucoma is the thickness of the central cornea. The present study leverages a unique blend of systems biology methods using BXD recombinant inbred mice and genome-wide association studies from humans to define a putative molecular link between a phenotypic risk factor (central corneal thickness) and glaucoma. We identified a transcription factor, POU6F2, that is found in the developing retinal ganglion cells and cornea. POU6F2 is also present in a subpopulation of retinal ganglion cells and in stem cells of the cornea. Functional studies reveal that POU6F2 is associated the central corneal thickness and with susceptibility of retinal ganglion cells to injury.

scholarly journals Stem Cell Transplantation Rescued A Primary Open-Angle Glaucoma Mouse Model

2020 ◽  
Author(s):  
Siqi Xiong ◽  
Ajay Kumar ◽  
Shenghe Tian ◽  
Eman E. Taher ◽  
Enzhi Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Retinal Ganglion Cells ◽  
Primary Open Angle Glaucoma ◽  
Therapeutic Potential ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Retinal Ganglion ◽  
Upregulated Genes

AbstractGlaucoma is a leading cause of irreversible blindness. In this study, we investigated if exogenous 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.

CITICOLINE APPLICATIONS AS A COMPLEX PRIMARY TREATMENT

2020 ◽  
Vol 6 (1) ◽  
pp. 18-22
Author(s):  
Kh. Abulkasimova ◽  
◽  
M. Karimova
Keyword(s):  
Retinal Ganglion Cells ◽  
Primary Open Angle Glaucoma ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Primary Treatment ◽  
Retinal Ganglion ◽  
Open Angle ◽  
Complex Therapy ◽  
Stabilizing Effect ◽  
Lipid Balance

This article is about primary open-angle glaucoma (POAG) which is a multifactorial degenerative disease that affects the optic nerve and subsequently leads to the loss of retinal ganglion cells (RGC) and their axons. Therefore, preparations with antioxidant and membrane-stabilizing effect, as well as ensuring restoration of lipid balance, are relevant in the complex therapy of POAG.

scholarly journals Some Aspects of Vascular Theory of Development and Progression of Primary Open-Angle Glaucoma (Literature Review). Part 1

2019 ◽  
Vol 16 (1) ◽  
pp. 12-18
Author(s):  
S. I. Makogon ◽  
A. S. Makogon
Keyword(s):  
Primary Open Angle Glaucoma ◽  
Ganglion Cells ◽  
Open Angle Glaucoma ◽  
Vascular Wall ◽  
Biologically Active ◽  
Retinal Ganglion ◽  
Open Angle ◽  
Hemostatic System ◽  
Plasma Proteolytic Systems ◽  
The Impact

The article presents a review of studies on various aspects of vascular theory of primary open-angle glaucoma (POAG) development and progression. The data of foreign and domestic scientists on the influence of hemodynamic disturbances in the glaucoma pathogenesis, including various levels: Central, regional and microcirculatory. Violations of the universal mechanism of vascular tone regulation, namely endothelial dysfunction are described. Vascular endothelium is a barrier between vascular wall and blood plasma. When the endothelium is damaged, its antithrombotic properties are transformed into a powerful prothrombotic potential. This leads to an imbalance between vasoconstrictors (endothelin) and vasodilators (nitric oxide). In addition, the release of biologically active substances with local neurotoxic effects. The authors noted an increase in the concentration of endothelin-1, studied its interaction with nitrogen oxide and considered its role in the occurrence of ischemia and the impact on the death of retinal ganglion cells. Scientists have noticed an increase in the level of Willebrand factor and increased platelet aggregation in patients with progressive glaucoma. As a possible cause of hemodynamic disturbances and glaucoma progression, the authors consider changes in blood rheological properties. In addition, the state of the three closely interacting components: the wall of blood vessels (primarily endothelium and subendothelial structures); cellular elements of blood (primarily platelets) and plasma proteolytic systems ensure the normal functioning of the hemostatic system. Changes in of these components state may affect the hemostatic system. Therefore, further study of various directions of vascular theory will help in understanding the etiopathogenesis of glaucoma.

scholarly journals Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma

2007 ◽  
Vol 179 (7) ◽  
pp. 1523-1537 ◽  
Author(s):  
Gareth R. Howell ◽  
Richard T. Libby ◽  
Tatjana C. Jakobs ◽  
Richard S. Smith ◽  
F. Campbell Phalan ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mouse Model ◽  
Retinal Ganglion Cells ◽  
Strong Evidence ◽  
Ganglion Cells ◽  
Lamina Cribrosa ◽  
Retinal Ganglion ◽  
Rich Region ◽  
Pattern Electroretinography ◽  
Axon Damage

Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wlds allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.

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