Stem cell treatment of degenerative eye disease

Abstract

Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment.

Figure 1

A schematic diagram showing the proposed mechanism by which MSCs exert their neurotrophic effects on the injured CNS, including the retina, through secretion of NGF, BDNF, NT-3, CNTF GDNF, VEGF, FGF and PDGF which engage TrK A, B and C, CNTFα, GFRα, VEGFR, FGFR1 and PDGFR receptors, respectively, leading to the activation of intracellular pathways for axon growth, axon growth disinhibition and neuroprotection, accounting for the functional recovery seen in animals receiving MSC transplants after CNS/retinal injury. Some ligand-receptor interactions lead to the activation of the same signalling pathways (abbreviations: BAD, bcl-2-associated death promoter; Bcl2, B-cell lymphoma 2; FGFR1, fibroblasts growth factor receptor 1; FRS2, fibroblast growth factor receptor substrate 2; GFRα, GDNF family receptor alpha; Grb2, growth factor receptor-bound protein 2; GSK-3β, glycogen synthase kinase-3β; IAPS, inhibitor of apoptosis; MAPK, mitogen-activated protein kinase; Mek, mitogen-activated protein kinase; PDK, phosphoinositide-dependant kinase; PKC, protein kinase C; PLCγ, phospholipase C-gamma).

Figure 2

A diagram showing the proposed way in which ESC/iPSC-derived RPE and photoreceptors can be used to treat AMD/photoreceptor degeneration. The left panel shows a rat retina immunohistochemically stained for cone annexin (cone photoreceptor marker; green), Brn3a (RGC marker; red) and DAPI (nuclear marker; blue) with the individual layers labelled (scale bar: 100 μm). On the right, RPE is represented together with photoreceptor loss in AMD and the potential for cell replacement in preventing visual decline and restoring vision.