Abstract
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.
Highlights
Because there is no effective therapy for irreversible damage to the optic nerve, many studies have attempted to improve the essential regenerative capacity of retinal ganglion cells (RGCs) [1]
We previously reported that the regulation of hypoxia-inducible factor 1-alpha (Hif1α) and growth-associated protein 43 (GAP43) of mesenchymal stem cells (MSCs) derived from human placenta (PSCs) promote axon survival in an optic nerve compression (ONC) model [22]
CHA15 human embryonic stem cells (ESCs) were differentiated into neural progenitor cells (NPCs) by treatments with 5 μM PKCβ inhibitor, and 1 μM DMH1 in the medium consisting of Dulbecco’s minimal Eagle’s medium (DMEM)/F12, 10 μg/mL human insulin, 9 μg/mL transferrin, and 14 ng/mL selenite (Figure 1A)
Summary
Because there is no effective therapy for irreversible damage to the optic nerve, many studies have attempted to improve the essential regenerative capacity of retinal ganglion cells (RGCs) [1]. We previously reported that the regulation of hypoxia-inducible factor 1-alpha (Hif1α) and growth-associated protein 43 (GAP43) of MSCs derived from human placenta (PSCs) promote axon survival in an optic nerve compression (ONC) model [22]. Neural progenitor cells (NPCs) have been found to be useful as a new cell therapy platform for various diseases [26] In this context, we investigated the safety and clinical efficacy of human pluripotent stem cell-derived NPCs in an ONC model
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