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iPSC-Derived Retinal Ganglion Cells: A New Tool in the Battle Against Optic Neuropathies

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Review of “Stepwise Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells Enables Analysis of Glaucomatous Neurodegeneration” from Stem Cells by Stuart P. Atkinson

Retinal ganglion cells (RGCs) serve as the connection between the eye and the brain and are the cell affected in optic neuropathies such as glaucoma. Therefore, RGC production from pluripotent stem cells (PSCs) sources could represent an exciting cell therapy. 

However, this process lacks reliable markers, and so the group of Jason S. Meyer (Indiana University Purdue University, Indianapolis, USA) set out to detail the differentiation of RGCs, and by doing so, allowed for the generation of RGCs from glaucoma patient-derived iPSCs [1]. The authors hope that this will serve as an in vitro model system for RGC development and disease progression, and also allow for the screening of drugs to treat glaucoma and other optic neuropathies.

To perform an unequivocal study of RGCs, the study initially sought to differentiate hPSCs through early neural and retinal progenitor intermediaries. This began with differentiation to the optic vesicle-like stage of retinogenesis and identification and enrichment of CHX10-positive retinal progenitor cells. After 40 days of differentiation, the authors noted the expression of retinal-associated transcription factors, including the RGC marker BRN3. However, there was no expression of genes associated with auditory [2] and somatosensory lineages [3] which can also express BRN3 and have confused previous studies. Encouragingly, the authors noted that further in vitro growth of such cells led to the appearance of morphological, phenotypic, and physiological [4] characteristics specific to RGCs, such as extensive MAP2-positive neurite extensions. 

This success spurred the authors on to next utilize induced pluripotent stem cells (iPSCs) from patients with a mutation in the OPTN gene which present with RGC degeneration. Following the differentiation scheme used previously, the study demonstrated the ability to generate BRN3-positive RGCs with “elaborate MAP2-positive neuronal morphologies and formation of complex neural networks” (See figure). OPTN mutant RGCs demonstrated elevated levels of cell death, although treatment with neuroprotective agents (e.g. BDNF or PEDF) reduced caspase-3 activation, suggesting that OPTN iPSC-derived RGCs may represent a great tool for pharmacological screening.

Hopefully, this comprehensive study will stand as a great platform for the start of studies into the differentiation and function of RGCs, and also for the study of RGCs affected in optic neuropathies such as glaucoma [5] and the creation of pharmacological screens for more effective neuroprotective agents. Head on over to the original article, where we hope you will be able to clearly see all the great data generated on this important cell iPSC-derived cell type.

References

  1. Ohlemacher SK, Sridhar A, Xiao Y, et al. Stepwise Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells Enables Analysis of Glaucomatous Neurodegeneration. STEM CELLS 2016;34:1553-1562.
  2. Koehler KR, Mikosz AM, Molosh AI, et al. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 2013;500:217-221.
  3. Chambers SM, Qi Y, Mica Y, et al. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat Biotechnol 2012;30:715-720.
  4. Velte TJ and Masland RH Action potentials in the dendrites of retinal ganglion cells. J Neurophysiol 1999;81:1412-1417.
  5. Egawa N, Kitaoka S, Tsukita K, et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 2012;4:145ra104.