Long-term neuronal survival, regeneration, and transient target reconnection after optic nerve crush and mesenchymal stem cell transplantation

Abstract

Background Retina 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. Methods We 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. Results rMSC 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. Conclusions We 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. Electronic supplementary material The online version of this article (10.1186/s13287-019-1226-9) contains supplementary material, which is available to authorized users.

Human mesenchymal stem cell therapy promotes retinal ganglion cell survival and target reconnection after optic nerve crush in adult rats

“…Here, we found that 14 days after optic nerve crush and vehicle injection, the number of Tuj1 + retinal neurons was dramatically reduced to 15.39% of the number in the control retina (1142 ± 49.46 Tuj1 + cells/mm 2 in control retinas; 117.8 ± 22.34 Tuj1 + cells/mm 2 in the vehicle group; Fig. 1 A, B, F), consistent with previous studies [ 5 , 6 , 8 , 31 , 50 ]. Treatment with hWJ-MSCs significantly increased RGC survival to 37.62% of the number in the control retina (429 ± 33.01 Tuj1 + cells/mm 2 in the hWJ-MSC group; Fig.…”

“…Previous studies from our group have shown that cell therapy with adult bone marrow-derived mononuclear cells (BMMC) increases RGC survival in an optic nerve crush model for a short time period, and some axons can reach and establish synapses in the SC [ 8 , 30 ]. Alternatively, our group has shown that mesenchymal stem cells (MSCs) remain in the rat vitreous body for at least 18 weeks, providing prolonged neuroprotection to RGCs [ 6 ] and inducing strong axonal regeneration up to their brain targets [ 31 ]. Also, MSCs have been shown to protect RGCs in models of ischemia/reperfusion [ 32 ] and ocular hypertension [ 33 – 35 ], among others.…”

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

“…Nevertheless, when implanted in the injured region, beside differentiation and integration onto the damaged tissue, therapeutic effect of MSCs could be due to different mechanisms: secretion of neurotrophic factors [146], astroglial activation and neurogenesis induction [147], axon growth [148], enhancement of synaptic and cortical interhemispheric connections [149], immunomodulatory and anti-inflammatory properties [150], and decrease of apoptosis and oxidative stress [151]. Many cells types secrete exosomes as key players in cell-cell communication: exosomes contain many bioactive molecules and can regulate the expression of genes associated to neuronal development and transcription factors [152].…”

Hepatocyte growth factor (HGF) and stem cell factor (SCF) maintained the stemness of human bone marrow mesenchymal stem cells (hBMSCs) during long-term expansion by preserving mitochondrial function via the PI3K/AKT, ERK1/2, and STAT3 signaling pathways

“…In recent years, several studies have focused on the various therapeutic applications of mesenchymal stem cells (MSCs), including cell transplantation for cartilage and bone repair [1,2] and neuronal regeneration [3,4], due to their ability to self-renew and differentiate into a variety of cell types. Furthermore, due to their low immunogenicity and ability to secrete immune factors or cytokines [5,6], MSCs have been studied and utilized in clinical trials for some immune-related diseases, such as chronic graft versus host diseases (cGVHD) [7] and Crohn's disease [8].…”