Cellular signaling and factors involved in Müller cell gliosis: Neuroprotective and detrimental effects

https://doi.org/10.1016/j.preteyeres.2009.07.001Get rights and content

Abstract

Müller cells are active players in normal retinal function and in virtually all forms of retinal injury and disease. Reactive Müller cells protect the tissue from further damage and preserve tissue function by the release of antioxidants and neurotrophic factors, and may contribute to retinal regeneration by the generation of neural progenitor/stem cells. However, Müller cell gliosis can also contribute to neurodegeneration and impedes regenerative processes in the retinal tissue by the formation of glial scars. This article provides an overview of the neuroprotective and detrimental effects of Müller cell gliosis, with accounts on the cellular signal transduction mechanisms and factors which are implicated in Müller cell-mediated neuroprotection, immunomodulation, regulation of Müller cell proliferation, upregulation of intermediate filaments, glial scar formation, and the generation of neural progenitor/stem cells. 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.

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.).

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