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Ben Mead, Ann Logan, Martin Berry, Wendy Leadbeater, Ben Scheven; Dental pulp, bone marrow and adipose-derived mesenchymal stem cell therapies for optic neuropathies. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2161.
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Retinal ganglion cells (RGC) and their axons are damaged in the optic neuropathies that develop after head trauma and in glaucoma. In this study, we compared the potential paracrine benefits of intravitreally grafted rat-, and human-derived dental pulp stem cells (DPSC), bone marrow-derived mesenchymal stem cells (BMSC) and adipose-derived stem cells (AMSC) as neuroprotective and axogenic therapies for axotomised adult rat RGC.
We used in vitro and in vivo axotomized adult rat RGC as experimental models to test the relative neurotrophic influence of the mesenchymal stem cells (MSC), monitoring RGC survival and neurite outgrowth/axon regeneration through immunocytochemistry/immunohistochemistry and optical computerized tomography.
All MSC types released an array of neurotrophic factors in culture including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF). Both rat- and human-derived DPSC secreted higher titres of NGF, BDNF, NT-3 and VEGF than BMSC and AMSC. When co-cultured with human-derived DPSC, axotomized RGC exhibited both increased survival (282.7 ± 17.1 RGC/well) and length of neurite outgrowth (236.7 ± 9.5 µm) compared to RGC cultured either alone (100.7 ± 9.5 RGC/well, 32.8 ± 1.4 µm), with BMSC (219 ± 28.4 RGC/well, 150.7 ± 24.1 µm) or with AMSC (200.0 ± 10.2 RGC/well, 101.1 ± 12.1 µm). This effect was significantly reduced with the addition of Fc blockers to the Trk/GDNF/VEGF receptors, suggesting it was mediated by multiple secreted neurotrophins. After optic nerve transection in adult rats, intravitreal DPSC transplants survived 21 days in the vitreous and promoted significant survival of RGC (27.9 ± 2.0 RGC/mm of retina) and regeneration of their axotomized axons (272.7 ± 37.1 at 100µm, 164.0 ± 16.9 axons/nerve at 1200µm from crush site) compared to untreated animals (6.9 ± 1.1 RGC/mm of retina; 67.5 ± 30.0 at 100µm, 14.2 ± 6.1 axons/nerve at 1200µm from crush site) and BMSC transplanted animals (16.2 ± 1.3 RGC/mm of retina; 139.4 ± 40.4 at 100µm, 67.3 ± 9.3 axons/nerve at 1200µm from crush site).
This study reveals the potential of MSC, in particular DPSC, as candidate intravitreal cellular therapies after retinal injury/disease by providing a supportive neuroprotective/axogenic trophic environment for compromised RGC.
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