Abstract
BackgroundRetina and/or optic nerve injury may cause irreversible blindness, due to degeneration of retinal ganglion cells. We and others have previously shown that the intravitreal injection of mesenchymal stem cells (MSCs) protects injured retinal ganglion cells and stimulates their regeneration after optic nerve injury, but the long-term effects of this therapy are still unknown.MethodsWe injected rat MSC (rMSC) intravitreally in adult (3–5 months) Lister Hooded rats of either sex after optic nerve crush. Retinal ganglion cell survival, axonal regeneration, and reconnection were analyzed 60 and 240 days after crush by immunohistochemistry for Tuj1, anterograde labeling with cholera-toxin B and by immunohistochemistry for nerve growth factor-induced gene A (NGFI-A, driven by light stimulation) in the superior colliculus after a cycle of light deprivation-stimulation. Visual behaviors (optokinetic reflex, looming response, and preference for dark) were analyzed 70 days after crush.ResultsrMSC treatment doubled the number of surviving retinal ganglion cells, preferentially of a larger subtype, and of axons regenerating up to 0.5 mm. Some axons regenerated to the lateral geniculate nucleus and superior colliculus. NGFI-A+ cells were doubled in rMSC-treated animals 60 days after crush, but equivalent to vehicle-injected animals 240 days after crush, suggesting that newly formed synapses degenerated. Animals did not recover visual behaviors.ConclusionsWe conclude that rMSC-induced neuroprotection is sustained at longer time points. Although rMSCs promoted long-term neuroprotection and long-distance axon regeneration, the reconnection of retinal ganglion cells with their targets was transitory, indicating that they need additional stimuli to make stable reconnections.
Highlights
The visual information is conveyed from the eye to the brain through the axons of retinal ganglion cells (RGCs), which form the optic nerve
The soma area of most RGCs was equal to or smaller than 150 μm2 in vehicle-injected animals (Additional file 1: Figure S1E), while a considerable number of cells bigger than 150 μm2 was detected in Rat mesenchymal stem cells (rMSCs)-injected animals (Additional file 1: Figure S1F), suggesting that rMSCs protected RGCs belonging to a larger subtype
We observed that the area of osteopontin+ cells in naïve rat retinas ranged from 150 to 500 μm2, with most cells measuring around 200– 350 μm2 (Additional file 1: Figure S1A-D), which was the same area range of most of RGCs that were protected by rMSC injection after optic nerve crush
Summary
The visual information is conveyed from the eye to the brain through the axons of retinal ganglion cells (RGCs), which form the optic nerve. The regeneration in PTEN knockout mice is due to the activation of the mammalian target of rapamycin (mTOR), which can be Mesentier-Louro et al Stem Cell Research & Therapy (2019) 10:121 stimulated by different strategies, leading to extensive axonal regeneration and partial functional recovery only when combined with other approaches [12,13,14,15]. Many of these pro-regenerative pathways are at least indirectly associated with tumor growth, raising concern about the clinical feasibility of their manipulation [16]. We and others have previously shown that the intravitreal injection of mesenchymal stem cells (MSCs) protects injured retinal ganglion cells and stimulates their regeneration after optic nerve injury, but the long-term effects of this therapy are still unknown
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