Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma
Highlights
► Intraocular cell transplantation can confer sustained, localized neuroprotection. ► Many stem cells, including MSCs can protect RGCs in experimental glaucoma. ► Cell grafts may simultaneously target multiple protective pathways. ► Elucidating mechanisms of neuroprotection may reveal new target pathways. ► Use of cell transplants as glaucoma therapy will require careful evaluation of safety.
Introduction
The pathophysiological mechanisms implicated in glaucomatous retinal ganglion cell (RGC) degeneration are thought to include a complex interplay between primary axonal injury, neurotrophic factor (NTF) deprivation, ischemia, oxidative stress, mitochondrial dysfunction, and/or inflammation (as recently reviewed [1, 2]). Developing novel treatments that act directly on RGCs to enhance survival by counteracting the various cellular and molecular mechanisms that promote RGC death could be a useful adjunct to intraocular pressure reduction for preserving vision in individuals with glaucoma [3]. Intraocular transplantation of cells that exhibit neuroprotective properties might be one approach to achieving this goal. Here, we will review the rationale for cell transplantation-based approaches to RGC neuroprotection and explore the multiple neuroprotective properties of two cell classes that have been studied extensively for this purpose: glial cells and mesenchymal stem cells (MSCs).
Section snippets
Cell transplantation for retinal ganglion cell neuroprotection
Stem cell transplantation holds promise for replacing neurons that are lost in human disease, including in the eye where subretinal stem cell and retinal progenitor-derived grafts have been used to achieve functional photoreceptor replacement in murine models of retinal degeneration [4, 5, 6]. Glaucoma presents a more formidable challenge, as replacement RGCs would need to integrate into the more complex circuitry of the inner retina and project a lengthy axon capable of synapsing at precise
Glial transplantation
A major physiological role of glia is neuronal support, so it is tempting to speculate that glial cell transplantation might promote neuronal survival. One glial cell class that has been studied extensively for this purpose is the olfactory ensheathing cell (OEC), which normally wrap unmyelinated axons of olfactory receptors as they course through the olfactory nerve to the olfactory bulb [10]. Early studies characterized the abilities of OECs to promote survival and regeneration of spinal cord
Mesenchymal stem cell transplantation
Mesenchymal stem cells (MSCs) are multipotent stromal cells capable of differentiating into a variety of cell types, including adipocytes, osteoblasts, and chondrocytes. Their physiologic role is thought to involve regulation and maintenance of the hematopoietic stem cell niche [31], but experimental studies report that they also possess the inherent ability to protect neurons throughout the CNS from numerous types of insults including trauma, ischemia, and inflammatory damage. MSCs can be
Conclusions
Given that glaucoma is a complex disease with multiple pathways and mechanisms contributing to optic nerve injury, an effective neuroprotective therapy may need to target multiple pathways simultaneously. Cell transplantation might offer a convenient way to accomplish this goal. The selection of an ideal cell type for this purpose will require careful consideration of both its inherent properties and those that might be synthetically engineered into the graft. While delivery of multiple NTFs is
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (43)
- et al.
The molecular basis of retinal ganglion cell death in glaucoma
Prog Retin Eye Res
(2012) - et al.
Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement
Ophthalmology
(2012) - et al.
Neurotrophic properties of olfactory ensheathing glia
Exp Neurol
(2003) - et al.
Neurotrophic factor delivery as a protective treatment for glaucoma
Exp Eye Res
(2011) - et al.
Neutralization of BDNF attenuates the in vitro protective effects of olfactory ensheathing cell-conditioned medium on scratch-insulted retinal ganglion cells
Cell Mol Neurobiol
(2011) - et al.
Combined effect of olfactory ensheathing cell (OEC) transplantation and glial cell line-derived neurotrophic factor (GDNF) intravitreal injection on optic nerve injury in rats
Mol Vis
(2010) - et al.
Manipulation of olfactory ensheathing cell signaling mechanisms: effects on their support for neurite regrowth from adult CNS neurons in coculture
Glia
(2003) - et al.
Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells
Glia
(2006) Circulation and axonal transport in the optic nerve
Eye (Lond)
(2004)- et al.
Effects of bone-marrow mesenchymal stem cells transplanted into vitreous cavity of rat injured by ischemia/reperfusion
Graefes Arch Clin Exp Ophthalmol
(2009)
Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function
Exp Neurol
Migration of neurotrophic factors-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging
Stem Cells
Transplantation of bdnf-secreting mesenchymal stem cells provides neuroprotection in chronically hypertensive rat eyes
Invest Ophthalmol Vis Sci
Current concepts in the pathophysiology of glaucoma
Indian J Ophthalmol
Retinal repair by transplantation of photoreceptor precursors
Nature
Restoration of vision after transplantation of photoreceptors
Nature
Transplantation of adult mouse IPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice
PLoS ONE
Stem cell therapy for glaucoma: possibilities and practicalities
Expert Rev Ophthalmol
Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants
Proc Natl Acad Sci USA
Neuroprotective effect of intravitreal cell-based glucagon-like peptide-1 production in the optic nerve crush model
Acta Ophthalmol
PNS-CNS transitional zone of the first cranial nerve
J Comp Neurol
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