Stem cells for neuroprotection in glaucoma

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Abstract

Stem cell transplantation is currently being explored as a therapy for many neurodegenerative diseases including glaucoma. Cellular therapies have the potential to provide chronic neuroprotection after a single treatment, and early results have been encouraging in models of spinal cord injury and Parkinson's disease. Stem cells may prove ideal for use in such treatments as they can accumulate at sites of injury in the central nervous system (CNS) and may also offer the possibility of targeted treatment delivery. Numerous stem cell sources exist, with embryonic and fetal stem cells liable to be superseded by adult-derived cells as techniques to modify the potency and differentiation of somatic cells improve. Possible neuroprotective mechanisms offered by stem cell transplantation include the supply of neurotrophic factors and the modulation of matrix metalloproteinases and other components of the CNS environment to facilitate endogenous repair. Though formidable challenges remain, stem cell transplantation remains a promising therapeutic approach in glaucoma. In addition, such studies may also provide important insights relevant to other neurodegenerative diseases.

Introduction

The possible neuroprotective effects of stem cell transplantation are a focus of active investigation in neuroscience at the present time. There are a number of studies where such treatments have shown promise in animal models of neurodegenerative disease and applying such techniques to glaucoma has a number of attractions. Glaucoma is well suited for such investigations as it is possible to directly visualize cellular transplants in vivo and, in addition, techniques to assess small changes in the structure and function of the eye are well developed. Such findings may also apply to other neurodegenerative diseases with similar pathologies. In addition, current treatments for glaucoma are limited mainly to reduction of intraocular pressure, which fails to prevent further deterioration in some glaucomatous eyes and necessitates the development of new treatment approaches. Methods that have the potential for prolonged therapeutic effects after a single treatment are particularly attractive.

In this chapter, we explore the potential use of stem cells for neuroprotection in the central nervous system (CNS) and, in particular, the challenges of using such techniques for glaucoma therapy. We also consider the implications of results obtained in glaucoma models for other neurodegenerative diseases.

Section snippets

Glaucoma as a model of neurodegenerative disease

Glaucoma is the most common neurodegenerative disease in the world, affecting approximately 80 million people or 1.2% of the global population (Quigley and Broman, 2006). Like many neurodegenerative diseases, glaucoma is characterized by the loss of a discrete neuronal cell population from the CNS. Similarities in the pathophysiological mechanisms of cell death appear to exist between glaucoma and other neurodegenerative diseases. For example, signs of oxidative stress, glutamate toxicity,

Why use stem cells for neuroprotective therapy?

It is reasonable to ask what advantages there may be in using stem cells, or their various derivatives, as a neuroprotective therapy in glaucoma rather than simply using a pharmacological approach. One distinct advantage cellular therapy could provide is chronic neuroprotection after a single treatment. Once integrated into the host tissue, the ideal cellular therapy would provide lifelong support for RGCs and attenuate visual field loss. A further benefit of a cell-based therapy may be the

Stem cell sources

Stem cells possess the ability to self-renew indefinitely and to differentiate into a variety of different cell types. In contrast, progenitor cells are generally considered a more restricted cell type, often multipotent but usually of limited proliferative capacity. For simplicity, in this chapter, we will use the term “stem cell” in its broadest sense to cover all precursor cell types. Stem cells exist within a wide array of tissues and at all developmental stages from embryogenesis to

Neuroprotection by transplanted stem cells

Numerous published examples exist where stem cell transplantation for neurodegenerative disease has led to structural and functional benefit in the absence of differentiation or functional integration on the part of the engrafted cells. In these cases, the effect is often attributed to neuroprotection of the endogenous surviving tissue. There are a number of mechanisms by which transplantation of stem cells can be neuroprotective, and each may hold potential therapeutic applications for

Enhanced neuroprotection by transplantation of modified stem cells

In addition to neurotrophic support by naive transplanted stem cells, the possibility of augmenting the neuroprotective effect by using genetically modified stem cells to deliver specific factors has been explored. This concept has attracted particular attention in stroke research. Many studies have demonstrated that transplantation of various stem cell types into the infarcted brain can ameliorate ischemic damage (Haas et al., 2005). In addition to these earlier studies, a number of groups

Endogenous stem cells

It is now understood that endogenous pools of neural stem cells proliferate in response to brain injury, particularly in response to stroke (Felling and Levison, 2003; Tai and Svendsen, 2004). Furthermore, it has been demonstrated that this proliferation may be enhanced via the exogenous application of growth factors (Nakatomi et al., 2002; Tureyen et al., 2005; Ninomiya et al., 2006) and drugs (Zheng and Chen, 2007). Previous research has primarily focused on the role that enhanced

Key challenges

Given that many of the cell-based therapies we have discussed are reliant on transplantation, one of the key hurdles to the development of such clinical treatments is finding an acceptable source of stem cells, or their derivatives, for this purpose. This problem has a number of facets, perhaps the most well-publicized of which is the ethical acceptability of using stem cells derived from human embryonic or fetal tissue for clinical therapies — an emotive issue that is unlikely to be resolved

Conclusion

Stem cell transplantation may be a promising approach to human glaucoma treatment if barriers related to the control of differentiation, integration, and long-term survival of grafted cells can be overcome, and if safety and efficacy can be demonstrated. In the short term, however, glaucoma models provide a very useful system in which to explore the neuroprotective potential of cellular transplantation where both degenerating and transplanted cells can be directly visualized.

Abbreviations

    CNS

    central nervous system

    ES

    embryonic stem

    GDNF

    glial cell line-derived neurotrophic factor

    IGF1

    insulin-like growth factor 1

    MSC

    mesenchymal stem cell

    PIGF

    placental growth factor

    RGC

    retinal ganglion cell

    VEGF

    vascular endothelial growth factor

Acknowledgments

The funding for our work in this field has been provided by the Gates Cambridge Trust, Fight for Sight, the Glaucoma Research Foundation, and the GSK Clinical Fellowship Program.

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    NDB and TVJ contributed equally to this chapter

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