scholarly journals Retinal Stem Cells Transplanted into Models of Late Stages of Retinitis Pigmentosa Preferentially Adopt a Glial or a Retinal Ganglion Cell Fate

2007 ◽  
Vol 48 (1) ◽  
pp. 446 ◽  
Author(s):  
Kriss Canola ◽  
Brigitte Ange´nieux ◽  
Meriem Tekaya ◽  
Alexander Quiambao ◽  
Muna I. Naash ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinitis Pigmentosa ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Retinal Ganglion ◽  
Late Stages ◽  
Retinal Stem Cells

scholarly journals Methods of Retinal Ganglion Cell Differentiation From Pluripotent Stem Cells

2014 ◽  
Vol 3 (3) ◽  
pp. 7 ◽  
Author(s):  
Katherine P. Gill ◽  
Alex W. Hewitt ◽  
Kathryn C. Davidson ◽  
Alice Pébay ◽  
Raymond C. B. Wong
Keyword(s):  
Stem Cells ◽  
Cell Differentiation ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Pluripotent Stem Cells ◽  
Retinal Ganglion

Methods of Retinal Ganglion Cell Differentiation From Pluripotent Stem Cells

2014 ◽  
Vol 3 (4) ◽  
pp. 2 ◽  
Author(s):  
Katherine P. Gill ◽  
Alex W. Hewitt ◽  
Kathryn C. Davidson ◽  
Alice Pébay ◽  
Raymond C. B. Wong
Keyword(s):  
Stem Cells ◽  
Cell Differentiation ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Pluripotent Stem Cells ◽  
Retinal Ganglion

Immunoregulation of retinal ganglion cell fate in glaucoma

2009 ◽  
Vol 88 (4) ◽  
pp. 825-830 ◽  
Author(s):  
Martin B. Wax ◽  
Gülgün Tezel
Keyword(s):  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Retinal Ganglion

scholarly journals Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1372
Author(s):  
Gülgün Tezel
Keyword(s):  
Neurodegenerative Disease ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Inflammatory Responses ◽  
Treatment Strategies ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Broad Perspective ◽  
Proinflammatory Mediators

Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cell (RGC) somas, degeneration of axons, and loss of synapses at dendrites and axon terminals. Glaucomatous neurodegeneration encompasses multiple triggers, multiple cell types, and multiple molecular pathways through the etiological paths with biomechanical, vascular, metabolic, oxidative, and inflammatory components. As much as intrinsic responses of RGCs themselves, divergent responses and intricate interactions of the surrounding glia also play decisive roles for the cell fate. Seen from a broad perspective, multitarget treatment strategies have a compelling pathophysiological basis to more efficiently manipulate multiple pathogenic processes at multiple injury sites in such a multifactorial neurodegenerative disease. Despite distinct molecular programs for somatic and axonal degeneration, mitochondrial dysfunction and glia-driven neuroinflammation present interdependent processes with widespread impacts in the glaucomatous retina and optic nerve. Since dysfunctional mitochondria stimulate inflammatory responses and proinflammatory mediators impair mitochondria, mitochondrial restoration may be immunomodulatory, while anti-inflammatory treatments protect mitochondria. Manipulation of these converging routes may thus allow a unified treatment strategy to protect RGC axons, somas, and synapses. This review presents an overview of recent research advancements with emphasis on potential treatment targets to achieve the best treatment efficacy to preserve visual function in glaucoma.

scholarly journals Genetic interplay between transcription factor Pou4f1/Brn3a and neurotrophin receptor Ret in retinal ganglion cell type specification

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Vladimir Vladimirovich Muzyka ◽  
Tudor Constantin Badea
Keyword(s):  
Transcription Factor ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Gene Dosage ◽  
Neurotrophin Receptor ◽  
Surrounding Tissue ◽  
Retinal Ganglion ◽  
Cell Fate Decisions ◽  
Type Specification

Abstract Background While the transcriptional code governing retinal ganglion cell (RGC) type specification begins to be understood, its interplay with neurotrophic signaling is largely unexplored. In mice, the transcription factor Brn3a/Pou4f1 is expressed in most RGCs, and is required for the specification of RGCs with small dendritic arbors. The Glial Derived Neurotrophic Factor (GDNF) receptor Ret is expressed in a subset of RGCs, including some expressing Brn3a, but its role in RGC development is not defined. Methods Here we use combinatorial genetic experiments using conditional knock-in reporter alleles at the Brn3a and Ret loci, in combination with retina- or Ret specific Cre drivers, to generate complete or mosaic genetic ablations of either Brn3a or Ret in RGCs. We then use sparse labelling to investigate Brn3a and Ret gene dosage effects on RGC dendritic arbor morphology. In addition, we use immunostaining and/or gene expression profiling by RNASeq to identify transcriptional targets relevant for the potential Brn3a-Ret interaction in RGC development. Results We find that mosaic gene dosage manipulation of the transcription factor Brn3a/Pou4f1 in neurotrophic receptor Ret heterozygote RGCs results in altered cell fate decisions and/or morphological dendritic defects. Specific RGC types are lost if Brn3a is ablated during embryogenesis and only mildly affected by postnatal Brn3a ablation. Sparse but not complete Brn3a heterozygosity combined with complete Ret heterozygosity has striking effects on RGC type distribution. Brn3a only mildly modulates Ret transcription, while Ret knockouts exhibit slightly skewed Brn3a and Brn3b expression during development that is corrected by adult age. Brn3a loss of function modestly but significantly affects distribution of Ret co-receptors GFRα1-3, and neurotrophin receptors TrkA and TrkC in RGCs. Conclusions Based on these observations, we propose that Brn3a and Ret converge onto developmental pathways that control RGC type specification, potentially through a competitive mechanism requiring signaling from the surrounding tissue.

scholarly journals Programmed Switch in The Mitochondrial Degradation Pathways During Human Retinal Ganglion Cell Differentiation from Stem Cells is Critical for RGC Survival

2019 ◽  
Author(s):  
Arupratan Das ◽  
Claire M. Bell ◽  
Cynthia A. Berlinicke ◽  
Nicholas Marsh-Armstrong ◽  
Donald J. Zack
Keyword(s):  
Stem Cells ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Cortical Neurons ◽  
Vision Loss ◽  
Degradation Pathway ◽  
Degradation Pathways ◽  
Retinal Ganglion ◽  
Human Stem Cells ◽  
Human Neurons

ABSTRACTRetinal ganglion cell (RGC) degeneration is the root cause for vision loss in glaucoma as well as in other forms of optic neuropathies. Genetic analysis indicated abnormal mitochondrial quality control (MQC) as a major risk factor for optic neuropathies. However, nothing is known on how MQC regulates human retinal ganglion cell (hRGC) health and survival. Human pluripotent stem cells (hPSCs) provide opportunity to differentiate hRGCs and understand the abnormal MQC associated hRGC degeneration in great detail. Degradation of damaged mitochondria is a very critical step of MQC, here we have used stem cell derived hRGCs to understand the damaged mitochondrial degradation pathways for hRGC survival. Using pharmacological methods, we have investigated the role of the proteasomal and endo-lysosomal pathways in degrading damaged mitochondria in hRGCs and their precursor stem cells. We find that upon mitochondrial damage with the proton uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP), hRGCs more efficiently degraded mitochondria than their precursor stem cells. We further identified that for degrading damaged mitochondria, stem cells predominantly use the ubiquitine-proteasome system (UPS) while hRGCs use the endo-lysosomal pathway. UPS inhibition causes apoptosis in stem cells, while hRGC viability is dependent on the endo-lysosomal pathway but not on the UPS pathway. This suggests manipulation of the endo-lysosomal pathway could be therapeutically relevant for RGC protection in treating glaucoma. Endo-lysosome dependent cell survival is also conserved for other human neurons as differentiated human cerebral cortical neurons also degenerated upon endo-lysosomal inhibition but not for the proteasome inhibition.SIGNIFICANCE STATEMENTUsing human stem cells we have shown a switch in the mitochondrial degradation pathway during hRGC differentiation where endo-lysosomal pathway becomes the predominant pathway for cellular homeostasis and hRGC survival which is also true for human cortical neurons. These findings suggest manipulation of the endo-lysosomal pathway could be therapeutically relevant for RGC protection in treating glaucoma as well as for other neurodegenerative diseases.

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