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

Pooja Teotia, Matthew Van Hook, Christopher S Wichman, R. Rand Allingham, Michael A. Hauser, Iqbal Ahmad

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2239-2252
Number of pages14
JournalSTEM CELLS
Volume35
Issue number11
DOIs
StatePublished - Nov 2017

Fingerprint

Induced Pluripotent Stem Cells
Retinal Ganglion Cells
Glaucoma
Alleles
Cell Differentiation
p16 Genes
Biological Phenomena
Survival
Neurites
Sirolimus
Regulator Genes
Stem Cells
Pathology
Phenotype
Genes

Keywords

  • Glaucoma
  • In vitro disease modeling/patient specific Induced pluripotent stem cell
  • RNA-Seq
  • Retinal ganglion cells
  • SIX6

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Modeling Glaucoma : Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities. / Teotia, Pooja; Van Hook, Matthew; Wichman, Christopher S; Allingham, R. Rand; Hauser, Michael A.; Ahmad, Iqbal.

In: STEM CELLS, Vol. 35, No. 11, 11.2017, p. 2239-2252.

Research output: Contribution to journalArticle

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