September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
iPSC-derived RPE disease model of dry age-related macular degeneration
Author Affiliations & Notes
  • Nady Golestaneh
    Ophthalmology, Georgetown University Medical Center, Washington, District of Columbia, United States
    Neurology, Georgetown University, Washington, District of Columbia, United States
  • Footnotes
    Commercial Relationships   Nady Golestaneh, None
  • Footnotes
    Support  BrightFocus M2014039
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 6058. doi:
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      Nady Golestaneh; iPSC-derived RPE disease model of dry age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6058.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : The purpose of this study is to investigate the mechanism of dry AMD. The induced pluripotent stem cells-derived retinal pigment epithelium (iPSC-RPE) from RPE of dry AMD donors and from skin of dry AMD live patients were used as in vitro models.

Methods : The iPSC-RPE were generated from RPE of dry AMD donors and age-matched normal donors, and from skin biopsies of dry AMD patients. Single nucleotide polymorphism (SNP) was performed to determine the AMD susceptibility and/or protective loci in all samples. Next-generation sequencing was performed to identify genes that were differentially expressed between AMD-RPE and normal RPE. The iPSC-RPE were characterized by gene and protein expression. Phagocytosis assay was performed to verify the function of iPSC-RPE cells. Electron microscopy (EM) imaging was performed to identify disease phenotypes. Mitochondrial activity was measured. Cytoplasmic glycogen concentration was determined. Cell viability and ROS production under normal and oxidative stress condition were analyzed. The Real-Time PCR was performed to delineate the dysfunctional pathways.

Results : AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE exhibited similar disease-relevant cellular phenotypes, as opposed to the normal iPSC-RPE that were devoid of disease phenotypes. Disintegrated mitochondria, increased number of autophagosoms and cytoplasmic lipid droplets were observed in all AMD iPSC-RPE. Mitochondrial activity was reduced in AMD iPSC-RPE. Increased susceptibility to oxidative stress and higher reactive oxygen species (ROS) production were observed in AMD iPSC-RPE. ARMS2/HTRA1 was associated with lower SOD2 expression . However, the deficiency in SOD2 expression under normal and stress conditions was also apparent in AMD RPE-iPSC-RPE with protective loci for ARMS2/HTRA1, but with history of long-term heavy smoking. PGC-1α expression was decreased in all AMD-iPSC-RPE compared to normal iPSC-RPE.

Conclusions : The AMD RPE-iPSC-RPE and AMD Skin iPSC-RPE both exhibit similar disease phenotypes and dysfunctions. While ARMS2/HTRA1 susceptibility loci could be associated with dysfunction in antioxidant defense, the epigenetic and environmental factors (smoking) could also cause the disease phenotypes in RPE. Our results suggest mitochondrial dysfunction caused by PGC-1α repression as the underlying disease mechanism in AMD-iPSC-RPE.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.


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