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Ben Mead, Ann Logan, Martin Berry, Wendy Leadbeater, Ben A Scheven; Dental Pulp, Bone Marrow and Adipose-Derived Mesenchymal Stem Cell Therapies for Glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2590.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cells (RGC) and their axons are damaged in glaucoma, a neurodegenerative disease characterised by progressive loss of RGC and ultimately, blindness. In this study, we compared the potential paracrine benefits of intravitreally grafted human-derived dental pulp stem cells (DPSC), bone marrow-derived mesenchymal stem cells (BMSC) and adipose-derived stem cells (ADSC) as neuroprotective cell therapies for glaucomatous adult rats.
We used in vitro axotomized adult rat RGC and an in vivo adult rat model of glaucoma as experimental models, with glaucoma induced in rats by bi-weekly intracameral injections of TGF-β, which induces trabecular meshwork fibrosis and raised intraocular pressure that results in a consistent 30% death of RGC over 35 days. To test the relative neurotrophic influence of different intravitreally implanted mesenchymal stem cells (MSC) in this model we monitored their effects on RGC survival through immunocytochemistry/immunohistochemistry, morphology through optical computerized tomography (OCT) and functionality of the retina and optic nerve through electroretinogram (ERG) and visual-evoked potential (VEP), respectively.
All MSC types released physiologically significant titres of an array of neurotrophic factors (NTF) when in culture, including NGF, BDNF, NT-3, GDNF, VEGF and PDGF, with the highest levels of NTF secreted by DPSC.<br /> When co-cultured with human-derived DPSC, axotomized RGC in mixed retinal cultures exhibited increased survival compared with RGC cultured without MSC, with BMSC or with AMSC. This effect was significantly reduced by the addition of specific Fc blockers to the NTF receptors for NGF, BDNF, NT-3, GDNF, VEGF and PDGF.<br /> When transplanted into the vitreous of glaucomatous rats, MSC survived for over 35 days but remained in the vitreal compartment, failing to penetrate and engraft within the retina. Immunohistochemical BRN3 staining in retinal sections demonstrated that MSC provided neuroprotection for RGC in our glaucoma model, whereas in control glaucomatous rats transplanted with dead MSC, the characteristic loss of RGC was observed.
This study reveals the potential of MSC, in particular DPSC, as candidate intravitreal cellular therapies to treat conditions associated with retinal degeneration, such as glaucoma, by providing a supportive neuroprotective trophic environment for compromised RGC.
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