Cellular signaling and factors involved in Müller cell gliosis: Neuroprotective and detrimental effects
Introduction
In the neural tissues of the central nervous system, reactivation of astrocytes (astrogliosis) occurs in response to all forms of nervous system injury and disease and has both protective and detrimental effects (Sofroniew, 2005). Gliosis is thought to represent a cellular attempt to protect the tissue from further damage and to preserve tissue function (Liberto et al., 2004). Protective and regenerative responses of astrocytes involve, among others, the production of neurotrophic factors, the release of antioxidant agents, the uptake of excess glutamate, the restoration of the blood–brain barrier, the promotion of neovascularization and remyelination, and the support of axonal regeneration and synaptic remodeling (Represa et al., 1995, Wilson, 1997, Privat, 2003, Liberto et al., 2004). However, astrogliosis may also contribute to neurodegeneration, and may impede regenerative processes by forming scar tissues that inhibit axon regeneration and neurite outgrowth (Bovolenta et al., 1992, Profyris et al., 2004).
Gliotic responses seem to be similar in the brain and neural retina. Müller cells are the principal glial cells of the neural retina, and play a wealth of crucial roles in supporting neuronal function (Bringmann et al., 2006). In response to virtually every pathological alteration of the retina, including photic damage, retinal trauma, ischemia, retinal detachment, glaucoma, diabetic retinopathy, and age-related macular degeneration, Müller cells become reactivated (Bringmann and Reichenbach, 2001, Bringmann et al., 2006). Reactive gliosis includes morphological, biochemical, and physiological changes of Müller cells; these alterations vary with type and severity of insult. Müller cells protect neurons after retinal injury, via release of neurotrophic factors and free radical scavengers, glutamate uptake, and facilitation of neovascularization (Bringmann et al., 2006, Bringmann et al., 2009). Müller cells may dedifferentiate to progenitor-like cells, and a subsequent (restricted) transdifferentiation to cells with neuronal phenotype (Fischer and Reh, 2001) may participate in tissue regeneration. However, gliotic alterations of Müller cells may also contribute to neuronal degeneration and edema development in the diseased retina (Bringmann et al., 2004, Bringmann et al., 2006), and the formation of glial scars may impede the repair and remodeling of the retinal tissue. While a recent review (Bringmann et al., 2006) described the involvement of Müller cells in normal retinal function and in different retinal diseases, the aim of the present review is to provide a more detailed survey of the cellular signaling mechanisms and (soluble) factors underlying and implicated in various aspects of Müller cell gliosis, i.e. neuroprotection, immunomodulation, regulation of Müller cell proliferation, upregulation of intermediate filaments, and glial scar formation. An account is provided on the potential of Müller cells to act as neurogenic cells in the injured mature retina, and a short perspective is provided on the possible use of Müller cells in retinal regeneration. Alterations in the glutamate recycling and the role of Müller cells in retinal edema were described in detail previously (Bringmann et al., 2004, Bringmann et al., 2009).
Section snippets
Protective effects of Müller cell gliosis
Gliosis of Müller cells has both cytoprotective and cytotoxic effects on retinal neurons (Bringmann and Reichenbach, 2001, Bringmann et al., 2006). Especially early after injury, gliosis is neuroprotective, and is thought to be a cellular attempt to limit the extent of tissue damage. The protective responses of Müller cells involve many different mechanisms, including buffering of elevated potassium levels (Bringmann et al., 2006), uptake of excess glutamate which is neurotoxic especially to
Unspecific and specific Müller cell responses
Müller cell gliosis is characterized by unspecific and specific responses to pathogenic stimuli; the former are independent and the latter are dependent on the kind of the stimulus. Müller cells show (at least) three important unspecific gliotic responses: cellular hypertrophy (Fig. 2B,C), proliferation, and upregulation of the intermediate filaments nestin, vimentin and glial fibrillary acidic protein (GFAP) (Figs. 2A,3A). The upregulation of GFAP is the most sensitive non-specific response to
Network of reactive gliosis
Müller cell gliosis is a component of a complex retinal response to pathogenic stimuli which may include a local inflammatory response characterized by activation of microglia, breakdown of the blood-retina barrier, and immigration of monocytes/macrophages, lymphocytes, and granulocytes into the retinal tissue and (in the case of photoreceptor degeneration) subretinal space. The infiltration of leukocytes into the retinal parenchyma (which contribute to the NO-mediated death of ganglion cells:
Immunomodulatory role of Müller cells
Müller cells play an active role in retinal immune and inflammatory responses. Under pathological conditions, Müller cells respond to inflammatory factors released by infiltrating blood-borne immune cells and activated microglia, act as immunocompetent cells, and are a source of inflammatory factors (Caspi and Roberge, 1989, Roberge et al., 1991, Drescher and Whittum-Hudson, 1996a, Drescher and Whittum-Hudson, 1996b).
Neuroprotective factors
Under pathological conditions, Müller cells are capable to protect photoreceptors and retinal neurons from cell death by the secretion of neurotrophic factors, growth factors, and cytokines. Various neurotrophic and growth factors, or combinations of the factors, are known to promote the survival of photoreceptors and inner retinal neurons. Receptors for BDNF, neurotrophin-3, GDNF, neurturin, CNTF, PEDF, and FGFs have been localized to photoreceptors and/or inner retinal neurons (Plouët et al.,
Müller cell proliferation
Unlike neurons, glial cells have the live-long capability to dedifferentiate und reenter the proliferation cycle. Hypertrophy and proliferation of Müller cells contribute to the formation of glial scars and the formation of periretinal fibrocellular membranes. Glial cells, in particular Müller cells, in association with blood-derived immune cells and factors within the vitreous are suggested to play a central role in the development of epiretinal membranes associated with proliferative
Müller stem cells
Retinal neurons have a limited capability to regenerate; apparently, only glial cells, quiescent progenitor cells at the ciliary marginal zone, and vascular cells maintain the capability to proliferate in the neural retina of adult warm-blooded vertebrates. Several lines of evidence have indicated a relationship among neural progenitor/stem cells and Müller cells; in fact, late progenitor cells were suggested to be immature Müller cells (Seigel et al., 1996, Walcott and Provis, 2003, Angénieux
Reactive Müller cells in therapeutic approaches
A proper understanding of the signaling mechanisms implicated in gliotic alterations of Müller cells is essential for the development of efficient therapeutic strategies that increase the supportive/protective and decrease the destructive roles of gliosis. Inhibition of Müller cell hypertrophy and glial scar formation may support tissue regeneration and neural integration of retinal transplants (Kinouchi et al., 2003), and may improve visual recovery after subretinal implantation of electronic
Acknowledgements
Some of the work presented in this review was conducted with grants from the Deutsche Forschungsgemeinschaft (GRK 1097/1, RE849/12, RE849/10, to A.R.) and the Bundesministerium für Bildung und Forschung (DLR/01GZ0703, to A.R.).
References (544)
- et al.
Identification of neural progenitors in the adult mammalian eye
Biochem. Biophys. Res. Commun.
(2000) - et al.
The localization of PGE2 receptor subtypes in rat retinal cultures and the neuroprotective effect of the EP2 agonist butaprost
Neurochem. Int.
(2009) - et al.
The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation
Biochim. Biophys. Acta
(1991) - et al.
Patterns of expression of brain-derived neurotrophic factor and tyrosine kinase B mRNAs and distribution and ultrastructural localization of their proteins in the visual pathway of the adult rat
Neuroscience
(2006) - et al.
Prostaglandin E2 receptor subtypes, EP1, EP2, EP3 and EP4 in human and mouse ocular tissues - a comparative immunohistochemical study
Prostaglandins Leukot. Essent. Fatty Acids
(2004) - et al.
CNS glial scar tissue: a source of molecules which inhibit central neurite outgrowth
Prog. Brain Res.
(1992) - et al.
Membrane conductance of Müller glial cells in proliferative diabetic retinopathy
Can. J. Ophthalmol.
(2002) - et al.
Müller cells in the healthy and diseased retina
Prog. Retin. Eye Res.
(2006) - et al.
Role of retinal glial cells in neurotransmitter uptake and metabolism
Neurochem. Int.
(2009) Cell-cell contact promotes DNA synthesis in retinal glia but not in fibroblasts
Exp. Cell Res.
(1983)
Growth in retinal glial cells in vitro is affected differentially by two types of cell contact-mediated interactions
Exp. Cell Res.
The role of extracellular matrix in CNS regeneration
Curr. Opin. Neurobiol.
A potent inhibitor of neurite outgrowth that predominates in the extracellular matrix of reactive astrocytes
Int. J. Dev. Neurosci.
Mechanical injury increases bFGF and CNTF mRNA expression in the mouse retina
Exp. Eye Res.
Glial cells as suppressor cells: characterization of the inhibitory function
J. Autoimmun.
Immunolocalization of CD44 in the dystrophic rat retina
Exp. Eye Res.
Distribution of CD44 in the retina during development and the rds degeneration
Dev. Brain Res.
Nerve growth factor (NGF), proNGF and NGF receptor-like immunoreactivity in BB rat retina
Brain Res.
Injury of Müller cells increases the incidence of experimental autoimmune uveoretinitis
Clin. Immunol. Immunopathol
Insulin-like growth factor-I expression is not increased in the retina of diabetic BB/W-rats
Diabetes Res. Clin. Pract.
Microglia/macrophages responses to kainate-induced injury in the rat retina
Neurosci. Res.
Bcl-2 proto-oncogene protein immunoreactivity in normally developing and axotomised rat retinas
Neurosci. Lett.
Treatment of retinal breaks with autologous serum in an experimental model
Ophthalmology
Thrombospondin-1 is a major activator of TGF-ß1 in vivo
Cell
Macrophage products IL-1α, TNFα and bFGF may mediate multiple cytopathic effects in the developing eyes of GM-CSF transgenic mice
Exp. Eye Res.
Neural stem cell properties of Müller glia in the mammalian retina: regulation by Notch and Wnt signaling
Dev. Biol.
Differential tumor necrosis factor expression by resident retinal cells from experimental uveitis-susceptible and -resistant rat strains
J. Neuroimmunol.
Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus
Am. J. Ophthalmol.
Oxygen distribution in the macaque retina
Invest. Ophthalmol. Vis. Sci.
Hypoxic regulation of vascular endothelial growth factor in retinal cells
Arch. Ophthalmol.
Presence of mitogen-activated protein kinase in retinal Müller cells and its neuroprotective effect ischemia-reperfusion injury
Neuroreport
Retinal gliopathy accompanying thioacetamide-induced liver insufficiency: light and electron microscopic observations
Acta Neuropathol.
Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy
Invest. Ophthalmol. Vis. Sci.
Sensitivities of ocular tissues to acute pressure-induced ischemia
Arch. Ophthalmol.
Morphological recovery in the reattached retina
Invest. Ophthalmol. Vis. Sci.
Platelet-derived growth factor plays a key role in proliferative vitreoretinopathy
Invest. Ophthalmol. Vis. Sci.
Epidermal growth factor is a neuronal differentiation factor for retinal stem cells in vitro
Stem Cells
Radioimmunoassay of a human growth factor for BALB/c-3T3 cells: derivation from platelets
Proc. Natl. Acad. Sci. U.S.A.
Heme oxygenase-1 induced in Müller cells plays a protective role in retinal ischemia-reperfusion injury in rats
Invest. Ophthalmol. Vis. Sci.
Dependence of collagen remodeling on α-smooth muscle actin expression by fibroblasts
J. Cell. Physiol.
Non-neural regions of the adult human eye: a potential source of neurons?
Invest. Ophthalmol. Vis. Sci.
Purification of mammalian cone photoreceptors by lectin panning and the enhancement of their survival in glia-conditioned medium
Invest. Ophthalmol. Vis. Sci.
Cytotoxicity of microglia
Glia
Angiostatic role of astrocytes - suppression of vascular endothelial cell growth by TGF-ß and other inhibitory factor(s)
Glia
Immunohistochemical characterization of retinal glial cell changes in areas of vascular occlusion secondary to diabetic retinopathy
Acta Ophthalmol. Scand.
Capillary closure secondary to retinal vein occlusion. A morphological, histopathological, and immunohistochemical study
Acta Ophthalmol. Scand.
Immunolocalization of ciliary neurotrophic factor receptor α (CNTFRα) in mammalian photoreceptor cells
Mol. Vis.
Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells
J. Neurosci.
The radial glia of Müller in the rat retina and their response to injury: an immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein
Exp. Eye Res.
Control of retinal and choroidal blood flow
Eye
Cited by (559)
TIMP3/Wnt axis regulates gliosis of Müller glia
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseModulation of TRPV4-mediated TNF-α expression in Müller glia and subsequent RGC apoptosis by statins
2024, Experimental Eye ResearchASCL1 induces neurogenesis in human Müller glia
2023, Stem Cell ReportsThe Rax homeoprotein in Müller glial cells is required for homeostasis maintenance of the postnatal mouse retina
2023, Journal of Biological Chemistry