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Abstract
Glaucoma, the leading cause of irreversible blindness worldwide, is a degenerative optic neuropathy for which current treatments slow the progression but do not cure the disease. While animal models are useful for studying underlying mechanisms of disease, there is a need for cell culture models of human glaucoma. With the advent of stem cell technology, building a glaucoma ‘disease-in-a-dish’ model using cells derived from human glaucoma patients is now viable. This review explores current progress and obstacles in generating retinal ganglion cells from human induced pluripotent stem cells, as well as the potential development of four different types of cell culture systems (single cell, co-culture, 3D retina and 3D optic nerve) that will be useful for interrogating cellular mechanisms, identifying therapeutic targets and screening drugs, with the future possibility of clinical translation.
Acknowledgements
The authors would like to thank Jonathan Simon Green for his artistic contribution in creating Figures 1 and 2.
Financial & competing interests disclosure
Y Ou has received the Research to Prevent Blindness Career Development Award and D Green is supported by the UCSF Academic Senate Committee on Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Glaucoma, the leading cause of irreversible blindness worldwide, is a degenerative optic neuropathy for which there is no cure. While retinal ganglion cell (RGC) death and axonal degeneration are known hallmarks of the disease, the mechanisms underlying disease pathogenesis are not yet well understood and there is a need for robust human cell culture models of glaucoma.
Stem cells hold great promise as new tools to model human glaucoma for the study of disease pathophysiology, investigation of genetic contributions to glaucoma and gene therapy, and high-throughput drug testing.
Human induced pluripotent stem cells can be directed to differentiate into most retinal cell types, recapitulating the sequence seen during in vivo development. New, more efficient ways to produce stem cell-derived RGCs are constantly being developed, and verifying identity and objectively comparing RGCs to their in vivo counterparts continue to be crucial.
The advent of human induced pluripotent stem cells and patient-derived disease-in-a-dish models has not only proven themselves useful in modeling a variety of diseases in different organ systems including retinal diseases of the eye, but also more recently in attempts to model glaucoma, although many obstacles still remain.
Human induced pluripotent stem cell-derived disease models can provide the researcher, and perhaps one day the clinician, with patient-specific human models of glaucoma. These models can be divided into four main types: single cell, co-culture, 3D retina and 3D bioengineered optic nerve .
The single cell model is best suited for studying causative mutations of glaucoma. It has already been used to investigate two hereditary forms of glaucoma involving mutations in the OPTN and TBK1 genes.
Co-culture models will be most useful for studying cell–cell interactions such as neurotoxic signaling by glia or axon guidance factors secreted by target cells.
The 3D retina model could help delineate cell–cell interactions between many cell types in their appropriate locations/retinal layers as well as retinal development. It may be better for studying specific subtypes of RGCs that show evidence of being differentially affected by elevated intraocular pressure.
A 3D optic nerve would be an excellent tool for investigating the biomechanical forces experienced by the optic nerve head with simulated intraocular pressure elevation. Additionally, it could serve to study axon guidance for potential regeneration applications and to highlight early axon degeneration and dysfunction seen along the optic nerve in disease states.