Hypoxia-Preconditioned Placenta-Derived Mesenchymal Stem Cells Rescue Optic Nerve Axons Via Differential Roles of Vascular Endothelial Growth Factor in an Optic Nerve Compression Animal Model

Abstract

Human placenta-derived stem cells (hPSCs) with the therapeutic potential to recover from optic nerve injury have been reported. We have recently demonstrated that hPSCs have protective abilities against hypoxic damage. To improve the capacity of hPSCs, we established a hypoxia-preconditioned strain (HPPCs) using a hypoxic chamber. The hPSCs were exposed to short-term hypoxic conditions of 2.2% O2 and 5.5% CO2. We also performed in vivo experiments to demonstrate the recovery effects of HPPCs using an optic nerve injury rat model. Naïve hPSCs (and HPPCs) were injected into the optic nerve. After 1, 2, or 4weeks, we analyzed changes in target proteins in the optic nerve tissues. In the retina, GAP43 expression was higher in both groups of naïve hPSCs and HPPCs versus sham controls. Two weeks after injection, all hPSC-injected groups showed recovery of tuj1 expression in damaged retinas. We also determined GFAP expression in retinas using the same model. In optic nerve tissues, HIF-1α levels were significantly lower in the HPPC-injected group 1week after injury, and Thy-1 levels were higher in the hPSC-injected group at 4weeks. There was also an enhanced recovery of Thy-1 expression after HPPC injection. In addition, R28 cells exposed to hypoxic conditions showed improved viability through enhanced recovery of HPPCs than naïve hPSCs. VEGF protein was a mediator in the recovery pathway via upregulation of target proteins regulated by HPPCs. Our results suggest that HPPCs may be candidates for cell therapy for the treatment of traumatic optic nerve injury.