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 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.

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 Dual SMAD inhibition and Wnt inhibition enable efficient and reproducible differentiations of induced pluripotent stem cells into retinal ganglion cells

2019 ◽  
Author(s):  
Venkata R. M. Chavali ◽  
Naqi Haider ◽  
Sonika Rathi ◽  
Vrathasha Vrathasha ◽  
Teja Alapati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Optic Nerve ◽  
Visual Field ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Visual Field Loss ◽  
Nerve Degeneration ◽  
Retinal Ganglion

AbstractGlaucoma is a group of progressive optic neuropathies that share common biological and clinical characteristics including irreversible changes to the optic nerve and visual field loss caused by death of retinal ganglion cells (RGCs). The loss of RGCs manifests as characteristic cupping or optic nerve degeneration, resulting in visual field loss in patients with Glaucoma. Published studies on in vitro RGC differentiation from stem cells utilized classical RGC signaling pathways mimicking retinal development in vivo. Although many strategies allowed for the generation of RGCs, increased variability between experiments and lower yield hampered the cross comparison between individual lines and between experiments. To address this critical need, we developed a reproducible chemically defined in vitro methodology for generating retinal progenitor cell (RPC) populations from iPSCs, that are efficiently directed towards RGC lineage. Using this method, we reproducibly differentiated iPSCs into RGCs with greater than 80% purity, without any genetic modifications. We used small molecules and peptide modulators to inhibit BMP, TGF-β (SMAD), and canonical Wnt pathways that reduced variability between iPSC lines and yielded functional and mature iPSC-RGCs. Using CD90.2 antibody and Magnetic Activated Cell Sorter (MACS) technique, we successfully purified Thy-1 positive RGCs with nearly 95% purity.

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.

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 Advances in Regeneration of Retinal Ganglion Cells and Optic Nerves

2021 ◽  
Vol 22 (9) ◽  
pp. 4616
Author(s):  
Fa Yuan ◽  
Mingwei Wang ◽  
Kangxin Jin ◽  
Mengqing Xiang
Keyword(s):  
Stem Cells ◽  
Retinal Ganglion Cells ◽  
Neurodegenerative Disorder ◽  
Ganglion Cells ◽  
Embryonic Stem ◽  
Retinal Ganglion ◽  
Somatic Cell Reprogramming ◽  
Induced Pluripotent

Glaucoma, the second leading cause of blindness worldwide, is an incurable neurodegenerative disorder due to the dysfunction of retinal ganglion cells (RGCs). RGCs function as the only output neurons conveying the detected light information from the retina to the brain, which is a bottleneck of vision formation. RGCs in mammals cannot regenerate if injured, and RGC subtypes differ dramatically in their ability to survive and regenerate after injury. Recently, novel RGC subtypes and markers have been uncovered in succession. Meanwhile, apart from great advances in RGC axon regeneration, some degree of experimental RGC regeneration has been achieved by the in vitro differentiation of embryonic stem cells and induced pluripotent stem cells or in vivo somatic cell reprogramming, which provides insights into the future therapy of myriad neurodegenerative disorders. Further approaches to the combination of different factors will be necessary to develop efficacious future therapeutic strategies to promote ultimate axon and RGC regeneration and functional vision recovery following injury.

scholarly journals A Safe GDNF and GDNF/BDNF Controlled Delivery System Improves Migration in Human Retinal Pigment Epithelial Cells and Survival in Retinal Ganglion Cells: Potential Usefulness in Degenerative Retinal Pathologies

2021 ◽  
Vol 14 (1) ◽  
pp. 50
Author(s):  
Alicia Arranz-Romera ◽  
Maria Hernandez ◽  
Patricia Checa-Casalengua ◽  
Alfredo Garcia-Layana ◽  
Irene T. Molina-Martinez ◽  
...  
Keyword(s):  
Cell Viability ◽  
Retinal Ganglion Cells ◽  
Neurotrophic Factor ◽  
Retinal Pigment Epithelial ◽  
Ganglion Cells ◽  
Retinal Pigment ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Retinal Ganglion ◽  
Pigment Epithelial

We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19; migration), and (RF/6A; angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients’ needs.

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