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Retinal ganglion cells can be generated from patient-specific, induced pluripotent stem cells and serve as an in vitro model for pharmacologic screening and pathophysiology studies.
Reviewed by Jason S. Meyer, PhD
Indianapolis-Researchers have successfully differentiated patient-derived induced pluripotent stem cells (iPSCs) into retinal ganglion cells (RGCs).
Now, they are looking forward to using this approach to facilitate drug-screening studies and to characterize the pathogenic mechanisms of disease progression in optic neuropathies, said Jason S. Meyer, PhD.
In a series of studies, the researchers first showed conclusively that cells derived from human PSCs were RGCs.
Then, through stepwise differentiation, they used skin fibroblasts harvested from a patient with glaucoma caused by a mutation in the Optineurin (OPTN) gene to generate RGCs, said Dr. Meyer, associate professor of biology, Indiana University Purdue University Indianapolis, and corresponding author of the paper [Ohlemacher SK, et al. Stem Cells. 2016;34:1553-1562].
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Next, they showed that the OPTN glaucoma patient-derived RGCs could serve as an in vitro model of the disease and could be protected from undergoing degeneration when treated with drugs known to have neuroprotective properties.
“Stem cell research involving differentiation of iPSCs is very appealing, because it lends itself to developing personalized medicine approaches,” Dr. Meyer said. “Although we and others previously showed iPSCs could be differentiated into cells with retinal characteristics that were presumably RGCs, our current study establishes the cells are truly RGCs.”
Furthermore, it is believed this work developing an in vitro model of glaucoma with patient-derived iPSCs opens the door to future research that will improve clinicians’ understanding of the pathways mediating progression of this blinding disease and finding new therapies through high-throughput drug screening, he noted.
Proof that cells differentiated from human PSCs were RGCs was achieved through characterization of a variety of physiological, phenotypic, and morphological characteristics.
Demonstration that the patient-derived iPSCS represented an in vitro model of glaucoma was based on evaluations showing that compared with RGCs derived from a nonglaucomatous control, they were much more likely to undergo apoptosis and degenerate, Dr. Meyer explained.
The potential to use the iPSC-derived RGCs for pharmacological screening was shown in experiments showing that treatment with two known neuroprotective agents, BDNF and PEDF, significantly reduced caspase-3 activation (a marker of apoptosis).
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“Although there are advantages to using animal models for drug candidate screening because in vivo studies allow safety assessments, the findings may not translate clinically because of differences between animal and human eyes,” Dr. Meyer said. “Pharmacological screening using the in vitro glaucoma model with iPSC-derived RGCs helps to bridge the gap between the animal and human systems.”
Looking farther into the future, Dr. Meyer acknowledged the possibility of using the iPSC-derived RGCs for transplantation to replace degenerated RGCs.
“It is not unreasonable to think about using these patient-specific cells as a source of spare parts to repopulate the retina,” he said. “However, success in that area involves overcoming a number of hurdles in terms of demonstrating that the cells survive, integrate, and function post-transplantation.”
Jason S. Meyer, PhD
Dr. Meyer has no competing interests to disclose.