scholarly journals Human Pluripotent Stem Cell-Derived Neural Progenitor Cells Promote Retinal Ganglion Cell Survival and Axon Recovery in an Optic Nerve Compression Animal Model

2021 ◽  
Vol 22 (22) ◽  
pp. 12529
Author(s):  
Mira Park ◽  
Hyun-Mun Kim ◽  
Hyun-Ah Shin ◽  
Seung-Hyun Lee ◽  
Dong-Youn Hwang ◽  
...  

Human pluripotent stem cell-derived neural progenitor cells (NPCs) have the potential to recover from nerve injury. We previously reported that human placenta-derived mesenchymal stem cells (PSCs) have neuroprotective effects. To evaluate the potential benefit of NPCs, we compared them to PSCs using R28 cells under hypoxic conditions and a rat model of optic nerve injury. NPCs and PSCs (2 × 106 cells) were injected into the subtenon space. After 1, 2, and 4 weeks, we examined changes in target proteins in the retina and optic nerve. NPCs significantly induced vascular endothelial growth factor (Vegf) compared to age-matched shams and PSC groups at 2 weeks; they also induced neurofilaments in the retina compared to the sham group at 4 weeks. In addition, the expression of brain-derived neurotrophic factor (Bdnf) was high in the retina in the NPC group at 2 weeks, while expression in the optic nerve was high in both the NPC and PSC groups. The low expression of ionized calcium-binding adapter molecule 1 (Iba1) in the retina had recovered at 2 weeks after NPC injection and at 4 weeks after PSC injection. The expression of the inflammatory protein NLR family, pyrin domain containing 3 (Nlrp3) was significantly reduced at 1 week, and that of tumor necrosis factor-α (Tnf-α) in the optic nerves of the NPC group was lower at 2 weeks. Regarding retinal ganglion cells, the expressions of Brn3a and Tuj1 in the retina were enhanced in the NPC group compared to sham controls at 4 weeks. NPC injections increased Gap43 expression from 2 weeks and reduced Iba1 expression in the optic nerves during the recovery period. In addition, R28 cells exposed to hypoxic conditions showed increased cell survival when cocultured with NPCs compared to PSCs. Both Wnt/β-catenin signaling and increased Nf-ĸb could contribute to the rescue of damaged retinal ganglion cells via upregulation of neuroprotective factors, microglial engagement, and anti-inflammatory regulation by NPCs. This study suggests that NPCs could be useful for the cellular treatment of various optic neuropathies, together with cell therapy using mesenchymal stem cells.

2020 ◽  
Vol 15 (10) ◽  
pp. 2163-2179
Author(s):  
Youngje Sung ◽  
Sang Min Lee ◽  
Mira Park ◽  
Hye Jeong Choi ◽  
Sukho Kang ◽  
...  

Aim: To assess the safety and feasibility of subtenon transplantation of human placenta-derived mesenchymal stem cells (hPMSCs) in Asian patients with traumatic optic neuropathy. Materials & methods: The survival of retinal ganglion cells in the rat retina was evaluated by monitoring the expression of Tuj1 and Gfap after optic nerve compression. Based on the preclinical data, we conducted a Phase I, open label, single center, nonrandomized clinical trial in four Asian traumatic optic neuropathy patients. The safety and ophthalmologic changes were evaluated. Results: The levels of Tuj1 and Gfap expression were significantly increased in the hPMSC treatment group compared with the sham group, suggesting a protective effect of hPMSCs on the optic nerve and retinal ganglion cells. There was no evidence of adverse proliferation, tumorigenicity, severe inflammation or other serious issues during the 12-month follow-up period. Visual acuity improved in all four patients. Conclusion: The results suggested that hPMSCs are safe and have potential utility in regenerative medicine. Clinical trial registration number: 20150196587 (Korean FDA), 2015-07-123-054 (IRB).


2019 ◽  
Author(s):  
Venkata R. M. Chavali ◽  
Naqi Haider ◽  
Sonika Rathi ◽  
Vrathasha Vrathasha ◽  
Teja Alapati ◽  
...  

AbstractGlaucoma is a group of progressive optic neuropathies that share common biological and clinical characteristics including irreversible changes to the optic nerve and visual field loss caused by death of retinal ganglion cells (RGCs). The loss of RGCs manifests as characteristic cupping or optic nerve degeneration, resulting in visual field loss in patients with Glaucoma. Published studies on in vitro RGC differentiation from stem cells utilized classical RGC signaling pathways mimicking retinal development in vivo. Although many strategies allowed for the generation of RGCs, increased variability between experiments and lower yield hampered the cross comparison between individual lines and between experiments. To address this critical need, we developed a reproducible chemically defined in vitro methodology for generating retinal progenitor cell (RPC) populations from iPSCs, that are efficiently directed towards RGC lineage. Using this method, we reproducibly differentiated iPSCs into RGCs with greater than 80% purity, without any genetic modifications. We used small molecules and peptide modulators to inhibit BMP, TGF-β (SMAD), and canonical Wnt pathways that reduced variability between iPSC lines and yielded functional and mature iPSC-RGCs. Using CD90.2 antibody and Magnetic Activated Cell Sorter (MACS) technique, we successfully purified Thy-1 positive RGCs with nearly 95% purity.


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