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Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities.

Publication ,  Journal Article
Teotia, P; Van Hook, MJ; Wichman, CS; Allingham, RR; Hauser, MA; Ahmad, I
Published in: Stem Cells
November 2017

Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls. The decrease in the number of RGC generation is accompanied by repressed developmental expression of RGC regulatory genes. The SIX6 risk allele RGCs display short and simple neurites, reduced expression of guidance molecules, and immature electrophysiological signature. In addition, these cells have higher expression of glaucoma-associated genes, CDKN2A and CDKN2B, suggesting an early onset of the disease phenotype. Consistent with the developmental abnormalities, the SIX6 risk allele RGCs display global dysregulation of genes which map on developmentally relevant biological processes for RGC differentiation and signaling pathways such as mammalian target of rapamycin that integrate diverse functions for differentiation, metabolism, and survival. The results suggest that SIX6 influences different stages of RGC differentiation and their survival; therefore, alteration in SIX6 function due to the risk allele may lead to cellular and molecular abnormalities. These abnormalities, if carried into adulthood, may make RGCs vulnerable in glaucoma. Stem Cells 2017;35:2239-2252.

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Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

November 2017

Volume

35

Issue

11

Start / End Page

2239 / 2252

Location

England

Related Subject Headings

  • Trans-Activators
  • Retinal Ganglion Cells
  • Male
  • Induced Pluripotent Stem Cells
  • Immunology
  • Humans
  • Homeodomain Proteins
  • Glaucoma
  • Gene Expression
  • Female
 

Citation

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MLA
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Teotia, P., Van Hook, M. J., Wichman, C. S., Allingham, R. R., Hauser, M. A., & Ahmad, I. (2017). Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities. Stem Cells, 35(11), 2239–2252. https://doi.org/10.1002/stem.2675
Teotia, Pooja, Matthew J. Van Hook, Christopher S. Wichman, R Rand Allingham, Michael A. Hauser, and Iqbal Ahmad. “Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities.Stem Cells 35, no. 11 (November 2017): 2239–52. https://doi.org/10.1002/stem.2675.
Teotia P, Van Hook MJ, Wichman CS, Allingham RR, Hauser MA, Ahmad I. Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities. Stem Cells. 2017 Nov;35(11):2239–52.
Teotia, Pooja, et al. “Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities.Stem Cells, vol. 35, no. 11, Nov. 2017, pp. 2239–52. Pubmed, doi:10.1002/stem.2675.
Teotia P, Van Hook MJ, Wichman CS, Allingham RR, Hauser MA, Ahmad I. Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities. Stem Cells. 2017 Nov;35(11):2239–2252.
Journal cover image

Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

November 2017

Volume

35

Issue

11

Start / End Page

2239 / 2252

Location

England

Related Subject Headings

  • Trans-Activators
  • Retinal Ganglion Cells
  • Male
  • Induced Pluripotent Stem Cells
  • Immunology
  • Humans
  • Homeodomain Proteins
  • Glaucoma
  • Gene Expression
  • Female