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Special Article |

Stem Cell Therapy for Ocular Disorders FREE

Leonard A. Levin, MD, PhD; Robert Ritch, MD; Julia E. Richards, PhD; Teresa Borrás, PhD
[+] Author Affiliations

From the Department of Ophthalmology and Visual Sciences, Universityof Wisconsin, Madison (Dr Levin); Department of Ophthalmology, New York Eyeand Ear Infirmary, New York (Dr Ritch); Department of Ophthalmology, New YorkMedical College, Valhalla (Dr Ritch); Department of Ophthalmology and VisualSciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor (DrRichards); and Department of Ophthalmology, University of North Carolina,Chapel Hill (Dr Borrás). The authors have no relevant financial interestin this article.


Arch Ophthalmol. 2004;122(4):621-627. doi:10.1001/archopht.122.4.621.
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  Cell injury or degeneration occurs in a number of blinding diseases.Therapy has classically consisted of preventing the initial injury or increasingthe resistance of cells to injury (cytoprotection). Recently, it has becomepossible to repopulate tissue compartments with stem cells. This article presentsa current summary of ocular stem cell research and applications to disease.It is based on presentations and discussions from the July 2002 internationalconference "Stem Cells and Glaucoma" sponsored by the Glaucoma Foundation.This meeting, the first of its kind, brought together ophthalmologists, geneticists,immunologists, and developmental biologists working on stem cell developmentand applications in both human and animal models.

Stem cells are undifferentiated cells able to divide indefinitely yetmaintain the ability to differentiate into specific cell types. They are ableto survive throughout the lifetime of the organism, while maintaining theirnumber, producing populations of daughter cells (transit amplifying cells)that can proceed down unique pathways of differentiation. Stem cells may beobtained from embryonic tissues, umbilical cord blood, and some differentiatedadult tissues. Although the potential for stem cell–based therapiesfor a variety of human diseases is promising, numerous problems remain tobe overcome, such as methods for obtaining, transplanting, inducing differentiation,developing function, and eliminating immune reactions.1 Stemcells have great potential value in treating eye diseases characterized byirreversible loss of cells, such as glaucoma and photoreceptor degeneration.

Although stem cells offer great opportunities for repair of the nervoussystem and the eye, their clinical use necessitates that we first gain anunderstanding of their proliferation, migration, differentiation, immunogenicity,and establishment of functional cell contacts.2 Itwill also be necessary to produce these cells in conditions that meet appropriatesafety and effectiveness standards. Our current understanding of the criticalfactors affecting stem cell behavior remains limited. Rapid progress is beingmade, and some of the first applications of stem cells to wound repair inhuman eyes have produced successes that offer hope for the use of stem cellsin other ophthalmologic conditions. In this article, we discuss current conceptsin stem cells and the eye and evaluate stem cell therapy in glaucoma as aparadigm for novel approaches to the treatment of eye disease.

The best understood stem cells are embryonic stem cells, which derivefrom early fetal development. To our knowledge, human embryonic stem cellswere first characterized in 1998.3 These cellsare pluripotent (able to differentiate into a wide variety of cell types)and relatively easy to maintain in culture, but they are necessarily allogeneic(from a different genetic donor) to the potential recipient. Embryonic stemcells are continuous cell lines and have the potential to differentiate intoretinal neurons, such as photoreceptors, so they might serve as an inexhaustiblesource of neural progenitors for stem cell therapy in the retina. Adult stemcells, as the name implies, are derived from mature organisms and are presentonly in restricted cellular compartments.4 Theyare multipotent (able to differentiate into a restricted number of cell types).Stem cells derived from the central nervous system (CNS) and ocular tissueshave been identified as sources for cells that may someday be used to repairdamaged brain, spinal cord, and retina. Stem cells within the eye have receivedattention because of the possibility that they could be obtained from a patientwith eye disease and used autologously.

Retinal Stem Cells

Stem cells have been discovered at the pigmented ciliary margin of theadult mouse retina.5 A mouse eye contains about100 of these cells, while the human eye contains about 10 000. They canbe isolated from eye bank eyes, even from elderly patients. Retinal stem cellsdo not differentiate to form brain cells yet are capable of producing allof the different retinal cell types. Although human brain stem cells growslowly, retinal stem cells require no growth factors and grow easily and rapidly,even in completely defined serum-free media. Retinal stem cells can also beisolated from fetal retinas.6 Both types ofretinal stem cells could lead the way for stem cell ocular therapies, suchas implanting photoreceptors grown in culture into the blind eye of an individualwith retinitis pigmentosa or other retinal degenerative disorders.

Anterior Segment Stem Cells

Limbal stem cells located in the basal limbal area are involved in renewalof the corneal epithelium. Deficiency due to aniridia, chemical burns, Stevens-Johnsonsyndrome, or pemphigoid leads to conjunctivalization, neovascularization,scarring, and ulceration of the cornea. Limbal stem cells can be transplantedby using autografts in cases of unilateral disease or allografts from relativesor cadaver eyes for bilateral disease. Recently, cultured limbal stem cellshave been used; a small biopsy specimen from a healthy limbus can be expandedex vivo and then grafted to an eye with stem cell deficiency.7 Systemicimmunosuppression is necessary in all cases in which allograft limbal stemcells are transplanted, although some patients may eventually achieve a stateof immunologic tolerance and immunosuppression can be discontinued. Futurestudies will focus on the potential use of adult pluripotent stem cells forocular surface reconstruction and also strategies for promoting a state oftolerance in allograft limbal transplantation.8,9

Autologous conjunctival biopsy specimens obtained in the superior fornix,where conjunctival stem cells reside, can be expanded in tissue culture byusing amniotic membrane as a carrier and can then be surgically transplantedto the ocular surface. These tissue equivalents have been used successfullyin conjunctival replacement after pterygium surgery and for repair of leakingfrom a scarred filtering bleb. This use of conjunctival stem cells suggestsadditional future applications for these tissue equivalents.

The corneal endothelium may contain regions for storage (most peripheral),regeneration (paracentral), and migration of stem cells. An area of cornealendothelial cells adjacent to the Schwalbe line may be able to transit amplifyingcells and slow-cycling cells.10 Endothelialcell density is markedly increased in this area, as compared with centralendothelial cell density.11,12

Although cell division in the normal primate trabecular meshwork israre, a niche for trabecular meshwork stem cells might exist at the Schwalbeline in monkeys. Cells at the Schwalbe line appear different from trabecularmeshwork cells, and cells with a similar phenotype to the former seem to migrateto the trabecular meshwork.13,14 Transplantationof trabecular meshwork stem cells to glaucomatous eyes might improve aqueousoutflow. Theoretically, trabecular meshwork stem cells might be isolated fromadult or embryonic trabecular meshwork. Embryonic stem cells are available,but there is a substantial risk that if transplanted into the chamber angle,they will not differentiate but rather continue to proliferate in the chamberangle. This would worsen, rather than improve, outflow. It is therefore necessaryto identify mechanisms to induce differentiation of embryonic stem cells tocells that express the trabecular meshwork phenotype.

To obtain large numbers of engrafted stem cells that differentiate ina desired way, strategies are needed to channel cells into desired phenotypes.15 Modification of the microenvironment and/or inhibitionof intracellular signaling cascades in engrafted cells will be needed forappropriate cell-specific differentiation into injured tissue.16

There are several likely sources of neural progenitors with retinalpotential that may make stem cell therapy for eye disease possible.17 Progenitors isolated from later stages of retinaldevelopment, which normally do not give rise to retinal ganglion cells (RGCs),can develop into RGCs in conducive conditions.18 Thesecells extend processes to tectal explants (a target for the RGC axon) andappear to function like RGCs. Stem cells derived from adult pigmented ciliaryepithelium are an excellent source of retinal progenitors because they candifferentiate along photoreceptors and RGC lineages.19 Anotherreadily accessible and promising source of neural progenitors for autologousstem cell therapy is the adult limbal epithelium (also discussed in the earliersubsection on anterior segment stem cells). Although nonneural in origin,progenitors from limbal epithelium can generate both neurons and glia.20

The influence of the age of the host on the fate of stem cells aftertransplantation has been studied in the Brazilian opossum, a small pouchlessmarsupial whose young are born in an immature state.21 Brainprogenitor cells from mice expressing green fluorescent protein as a markerwere transplanted via intraocular injection into developing and mature opossumeyes.22 These cells differentiated in hostretinas, often displaying morphologies characteristic of RGCs, amacrine cells,bipolar cells, and horizontal cells. Transplanted cells generally followedthe architectural organization of the host eyes. The greatest morphologicalintegration and differentiation was observed in the youngest host eyes, withlittle integration in mature eyes. Transplanted brain progenitor cells maybe capable of responding to local microenvironmental cues that promote theirdifferentiation and integration.

Gene expression analysis can be used to determine the genes involvedin the transition from the multipotent to the differentiated state. New retinalcells are continually added at the ciliary marginal zone in fish and amphibians,23 and it is possible to study the underlying molecularmechanisms of stem cells by comparing gene expression profiles between undifferentiatedand differentiated states or between multipotent and nonmultipotent states.2426

Tissue injury provides a host of factors that influence the fate ofimplanted stem cells and restricts their terminal lineages.16 Forexample, adult rat hippocampal neuronal progenitor cells have been transplantedinto the vitreous of glaucomatous rats in the hope that they would repopulatethe retina as RGCs. Some of the progenitor cells injected into the vitreousexpressed the neuronal tissue-specific microtubule-associated protein 2, whichsuggests that they start to develop into a neuronal phenotype (D. S. Sakaguchi,PhD, et al, unpublished data, 2003).

Adult human neural progenitor cells grafted to diseased hosts can expressmature neuronal markers, send processes to the appropriate plexiform layer,and extend neurites into the optic nerve.27 Inspecific developmental and injury conditions, brain-derived cells can differentiateinto cells similar to retinal neurons. However, in the mature (postmitotic)retina, this transformation is difficult to achieve. Local microenvironmentalcues influence phenotypic differentiation of grafted cells. Retinal stem cellsderived from mice expressing green fluorescent protein can develop into photoreceptorsand bipolar cells in vitro and in vivo.28 Withthe development of tissue engineering, retinal stem cells impregnated intopolymers might be grafted into the subretinal space.

Neural stem cell spheres have been injected into the vitreous of DBA/2Jmice, which have hereditary pigmentary glaucoma (M. J. Young, PhD, et al,unpublished data, 2003). In 14-month-old mice with mild depletion of theirRGCs, some transplanted cells entered the retina, elaborated processes, expressedneurofilaments, and actually sent processes into the plexiform layer. At 4months after transplantation, fibers were seen entering the optic nerve head.

Studies of stem cells in lower animals may provide insights to theirapplication in mammals. The Drosophila melanogaster ovaryprovides an attractive model to study stem cell biology because both stemcells and their surrounding cells have been well defined.29 Manystem cell properties and relationships to their microenvironments, or niches,can be effectively studied at molecular and cellular levels. This Drosophila system revealed critical issues in stem cell research, includingthe importance of the niche within which the stem cells and daughter cellsdifferentiate or remain unchanged, the ability to identify individual geneproducts of importance to differentiation status, and the opportunities touse bioinformatics to apply findings from a model to the study of humans.

As a fish grows, so does its CNS, including the retina. Retinal growthis partly due to the continual generation of new neurons. Furthermore, unlikeinjury in human nervous tissue, injury to the fish retina is repaired by regenerativeneurogenesis.30 Persistent and injury-inducedneurogenesis in the fish retina is due to the presence of stem cells thatperpetually reside in this tissue. Studies are under way to identify the genesexpressed by retinal stem cells and the molecules that regulate their neurogenicactivity, both during normal growth and after injury.31,32 Knowledgeof how these cells maintain their ability for neurogenesis may eventuallybe applicable to human cells.

The only treatment proved for glaucoma is pharmacological or surgicallowering of the intraocular pressure, but disease in many patients progressesdespite treatment. Even if new treatments were developed that could stop allfuture development of visual field loss, there would still be a substantialneed to deal with the profound visual field losses in millions of people whohave had glaucoma in the past. Neuroprotection of RGCs and their axons33 is an alternate treatment being investigated in randomizedcontrolled trials.34 Other potential treatmentsfor glaucoma are vaccination with antigens that can induce protective autoimmunity35 and improvement of ocular blood flow.36

There are at least 3 potential targets for stem cell therapy in glaucoma:the RGC, the optic nerve head, and the trabecular meshwork. So far, most workhas focused on replacing RGCs because their death is the final common pathwayfor visual loss in glaucoma and other optic neuropathies. Because human RGCsare mammalian CNS neurons that cannot divide and differentiate to replaceother cells lost from disease, blindness from glaucoma is irreversible. Findinga way to differentiate stem cells into RGCs and allow them to connect to theirappropriate targets would be a major step in repopulating the neurons lostin glaucoma. The main issues to be resolved are survival and differentiationof the stem cell, maintaining the state of the surrounding microenvironment,extension of axons into the optic nerve, establishment of functional connectionsin the lateral geniculate nucleus, and appropriate activation of transsynapticallyconnected cortical targets.

The RGC precursor cells introduced into the retina extend processesinto the optic nerve head.27 The need to establisha functional network communicating information to the brain makes the problemof stem cell replacement of RGCs especially complex. However, because patientslose a substantial portion of their RGCs before developing functional deficits,there is hope that a limited amount of restoration might have a large effecton visual capability.

Efforts to repair the trabecular meshwork could theoretically improveintraocular pressure regulation. Restoration of the entire trabecular meshworkmight not be needed, and simple replacement of corneoscleral cells might sufficebecause juxtacanalicular cells are not depleted in late stages of glaucoma.37 Although eye bank eyes might constitute a plentifulsource of trabecular meshwork cells, it remains to be seen whether rejectionof allogeneic cells would be a problem.

A third target for cellular repletion is the optic nerve head, whichundergoes substantial remodeling and biochemical change in glaucoma. Issuesto be dealt with in the region of the optic nerve head include excavation,activation of astrocytes, secretion of nitric oxide, vascular complications,and loss of cellularity.3840 Progressionof glaucomatous optic neuropathy in the presence of what appears to be clinicallyadequate lowering of intraocular pressure may reflect structural and functionalchanges of optic nerve head cells. Repopulating these cells with stem cell–derivednormal astrocytes and fibroblasts might be an alternate therapy for glaucoma—onethat does not require complex axonal pathfinding.

The optimal source of stem cells for a particular therapy is a majorissue. Not all stem cell types can be induced to differentiate into all ofthe cell types needed to treat glaucoma. It is encouraging that a number ofdifferent sources and types of stem cells and precursor cells have been identifiedfrom which relevant cell types for ocular stem cell therapy can be derived.These include not only fetal stem cells but also cells from brain, limbus,conjunctiva, corneal endothelium, and retina. One question that has not yetbeen addressed is whether stem cells are needed at all, or whether at leastsome problems in either the optic nerve head or the trabecular meshwork couldbe solved by simply transplanting young healthy differentiated cells intothe damaged eye.

Another approach to improving the local environment could come throughgenetic modification of cells before they are introduced. Successful use ofsuch approaches will require more work on determining which genetic modificationsare needed and also on overcoming problems with gene silencing that can happennot only after differentiation but also in some cases in the course of passagingcells as they are being grown for use. In the end, it seems likely that sometype of "nurse" cells that clean up the environment or provide supportingfactors will need to precede or accompany the primary cells being restored.In addition, protection of the fragile new cells may also arise from workon a vaccination approach to recruitment of cells from the immune system withneuroprotective functions.

Safety

There are strict rules for the conditions in which stem cells must begrown if they are destined for therapeutic use. Cells must be grown withoutserum and without the use of cell feeder layers, something that would potentiallycomplicate maintenance of at least some stem cell types that require othercell types in their local niche to maintain an intermediate state of differentiation.With the substantial amount of work required for approval to use a given cellline, it will be essential that such cells can be grown in large amounts whilemaintaining a particular stage of multipotent development. In addition, thecells must differentiate in completely defined conditions, their proliferationafter transplantation must be shut down, and they must perform the desiredfunctions while remaining localized to their site of targeting.

Microenvironment of the Transplanted Stem Cell

Another critical issue is that of the environment into which replacementcells will be introduced. The processes by which stem cells settle, differentiate,and extend axons in an adult eye do not recapitulate what happens during development,and the environment into which they are introduced may be hostile, as comparedwith the environment in which the original developmental processes took place.Restricted ability of neural implants to survive, migrate, and reestablishneuronal connections with the host environment has limited the success ofneural transplantation. It is unclear whether the postnatal trophic supportis sufficient to maintain stem cell survival41 orwhether scaffolding such as glial cells or extracellular matrix will adequatelyprotect the new axons that are attempting to make connections and transmitimpulses. Pretreatment of the injured tissue with growth factors such as neurotrophinsor repletion of supporting cells such as astrocytes or other cells producingtrophic or differentiating factors could greatly assist the survival of thenew cells in a previously hostile environment. The ability of transplantedneural graft cells to migrate and integrate into the host retina can be influencedby intrinsic properties of implant cells, as well as by factors in the hostretinal environment.

Continued Progression of Disease

Not only will the differentiated stem cell face a hostile environmentafter transplantation, but it also may be just as susceptible to the diseaseas the original cell. For example, a repopulated RGC in an eye with advancedglaucoma may not survive because of the underlying pathophysiology of thedisease. If it took many years for the adverse environment to kill the RGCs,the newly transplanted RGCs might survive longer, and the restoration of opticnerve function could last many years. If not, the restored cells might soondie unless steps are first taken to correct the environment, which is a morecomplex problem. Thus, the problem of preexisting injury in a diseased eyenecessitates that the damage from the surrounding environment be repairedin addition to replacing the primary cells of interest.

Pathfinding

The optic nerve carries axons from RGCs to targets in the lateral geniculatenucleus in a retinotopic mapping. For the injured optic nerve to be restored,there has to be pathfinding of transplanted retinal stem cells within theretina that migrate to the appropriate cellular location and send axons tothe optic nerve head, then through the nerve, 50% crossing at the chiasm,and eventually to a correct location in the lateral geniculate nucleus.42,43 Retinal glial cells, including astrocytesand Müller cells, are the guardians of the retinal cell layers. In thehost retina, they play an essential role in preventing graft cell migrationand integration. It may be possible to guide the migration of transplantedneural stem cells by selectively manipulating glial cell properties in thehost retinal environment. Ensuring crossing at the chiasm and precise arrivalat axonal targets remains a difficult problem.44,45

Remyelination

Not only is it necessary for RGCs to reach their appropriate targets,but physiological axonal conduction velocity and energy efficiency also requirethe presence of myelin. Our knowledge of remyelination in adult human CNSderives from the extent, or lack thereof, of remyelination observed in multiplesclerosis. This observation raises a number of issues regarding the potentialrole of progenitor cells in replacing injured myelin and oligodendrocytesin adult human CNS. Remyelination occurs in acute rather than chronic multiplesclerosis lesions. Oligodendrocyte progenitor cells can be identified in regionsof active multiple sclerosis lesions but without apparent increase in numbers,as compared with findings in normal brain tissue.46 Atissue is whether the remyelinating cells are derived from a pool of glial-restrictedprogenitor cells or from multipotent stem cells that migrate from subependymalregions. The apparent failure of ongoing remyelination in multiple sclerosiscould reflect a number of factors, including exhaustion of progenitor cells,lack of trophic signals, injured axons being unreceptive to remyelination,and selective immune injury of the progenitors.47,48 Theseissues will need to be understood for effective remyelination of the opticnerve.

Immune Response

Allogeneic stem cells are potential targets for the immune system, andtheir use may be hindered by humoral or cell-mediated rejection. This maybe tempered by the relatively immune-privileged nature of the eye. Althoughthe existence of stem cells in the adult eye or other organs offers the possibilityof bypassing allogeneic rejection through use of the patient's own stem cells,such cells might carry whatever defect initially predisposed the eye to glaucomaand therefore fail to correct the problem.

There is ample precedent for research in stem cell therapy for neurodegenerativedisease. A good example is motor neuron disease. In animal models of amyotrophiclateral sclerosis, human embryonic brain–derived cells produce rapidand profuse motor neuron growth when engrafted into the ventral horn of thespinal cord. Transplanted embryonic brain–derived cells acquire immunohistochemicalmarkers of mature neurons and astrocytes and send axonal processes to theperiphery. This process allows paralyzed animals to move their hind limbsand walk.

The same will likely be true for using stem cells for ophthalmic disease.Precursor cells can settle in the retina, differentiate into RGCs, connectwith afferent neurons in the inner plexiform layer, and grow into the opticnerve head. Many details need to be worked out about the use of such cellsto restore the complex delicate neural network of the eye. Not only cellularregrowth but also establishment of functional connections to the lateral geniculatebody will be required.

There are at least 5 different areas in which progress needs to be achieved.First, more needs to be known about precursor cells for any given cell typeand about their production of essential factors, which may mean identificationof stem cells that can differentiate into cell types that can live (eg, inthe optic nerve head) and produce the appropriate factors. Alternatively,it may mean genetic modification of cells to achieve expression of genes encodingsuch factors. Desired functions include interfering with apoptosis, inhibitingfactors in amacrine cells, and production of trophic factors.

Second, much more needs to be known about potential sources of stemcells that could be developed in appropriate conditions and that could beapproved for therapy. This includes the need to explore embryonic stem cells,brain stem cells, ocular stem cells, and even the transplantation of sometypes of mature differentiated cells.

Third, microenvironments need to be identified in which stem cells canproliferate; differentiate; engraft; migrate; and, once they are in the rightstate and place, shut down proliferation. This may include the need to understandmore about other cell types in the surrounding environments and on the topographicmap of the target region.

Fourth, study of naturally regenerating systems such as teleost or chickeye offer the chance to identify antagonists for inhibitors of regenerationin the retina and to identify the genes involved in growth and differentiationearly in development, when the ability of the mammalian retina to regeneratehas not yet been shut down.

Fifth, even some of the simplest experiments on transplantation of trabecularmeshwork cells have yet to be performed, and little is known about any potentialstem cells or precursor cells from which the trabecular meshwork might berevived.

Although preliminary results have been achieved on many different frontsin applying stem cell technology to eye disease, a tremendous amount of workremains. Some of the main issues are identification of the optimal precursorcell types, establishment of growth and differentiation conditions that meetsafety and effectiveness standards, and the manipulation of the surroundingenvironment to allow transplanted cells to survive and function. Althoughtransplanted neuronal precursors can connect into the inner plexiform layerand optic nerve head, precisely directing their axons to appropriate targetsremains to be demonstrated. Substantial progress in this and other areas needsto be achieved, particularly with respect to diseases like glaucoma and otheroptic neuropathies, before accurate reassembly of the complex visual pathwayswill be achieved.

Corresponding author: Leonard A. Levin, MD, PhD, Department of Ophthalmologyand Visual Sciences, University of Wisconsin Medical School, 600 HighlandAve, Madison, WI 53792-4673.

Submitted for publication February 4, 2003; final revision receivedJuly 15, 2003; accepted August 25, 2003.

Glaucoma Foundation Meeting Attendees

The Glaucoma Foundation held a meeting entitled "Stem Cells and Glaucoma"in Chicago, Ill, July 26-27, 2002. The meeting organizers and moderators wereTerete Borrás, PhD (University of North Carolina at Chapel Hill, ChapelHill, NC), Leonard A. Levin, MD, PhD (University of Wisconsin, Madison, Wis),Julia E. Richards, PhD (University of Michigan, Ann Arbor, Mich), and RobertRitch, MD (New York Eye and Ear Infirmary, New York, NY). Participants includedJ. Wayne Streilein, MD (President, Schepens Eye Research Institute, Boston,Mass), Theodore Krupin, MD (Clinical Professor of Ophthalmology, NorthwesternUniversity School of Medicine, Evanston, Ill), Derek van der Kooy, PhD (Professorof Anatomy and Cell Biology, Faculty of Medicine, University of Toronto, Ontario,Canada), Scott Whittemore, PhD (Professor of Neurological Surgery, Universityof Louisville School of Medicine, Louisville, Ky), Ryo Kubota, MD, PhD (AssistantProfessor, Department of Ophthalmology, University of Washington, Seattle),Young Kwon, MD, PhD (Associate Professor of Clinical Ophthalmology, Departmentof Ophthalmology, University of Iowa, Iowa City), Michael J. Young, PhD (Director,Minda de Gunzburg Research Center for Retinal Transplantation, Harvard MedicalSchool, Boston, Mass), Simon John, PhD (Associate Investigator, Jackson Laboratories,Howard Hughes Medical Institute, Bar Harbor, Me), Ting Xie, PhD (AssistantScientist, Stowers Institute for Medical Research, Kansas City, Mo), PeterHitchcock, PhD (Associate Professor of Ophthalmology and Visual Sciences andDevelopmental Biology, University of Michigan, Ann Arbor, Mich), Iqbal Ahmad,PhD (Associate Professor of Ophthalmology and Pharmacology, University ofNebraska Medical Center, Omaha), Donald Sakaguchi, PhD (Associate Professorof Zoology and Genetics, Iowa State University, Ames, Iowa), Jeffrey Rothstein,MD, PhD (Professor of Neurology and Neuroscience, Johns Hopkins University,Baltimore, Md), Dong Feng Chen, PhD (Assistant Professor, Department of Ophthalmology,Harvard University, Boston, Mass), Henry Edelhauser, PhD (Director of OphthalmicResearch, Emory Eye Center, Atlanta, Ga), Ernst Tamm (Professor of MolecularAnatomy and Embryology, Department of Anatomy, University of Erlangen-Nürnberg,Erlangen, Germany), Jack Antel, MD (Professor of Neurology, Montreal NeurologicInstitute, Quebec, Canada), Ali Djalilian, MD (National Eye Institute, Bethesda,Md), Michal Schwartz, PhD (Professor of Neuroimmunology, Weizmann Instituteof Science, Rehovot, Israel), Roger Beuerman, PhD (Scientific Director, SingaporeEye Research Institute, Singapore), William W. Hauswirth, PhD (Universityof Florida, Gainesville), Paul Kaufman, MD (University of Wisconsin, Madison),Erin B. Lavik, ScD (Massachusetts Institute of Technology, Cambridge, Mass),James C. Tsai, MD (Columbia University, New York, NY), Abbot F. Clark, PhD(Alcon Research Ltd, Fort Worth, Tex), John Donello, PhD (Allergan Inc, Irvine,Calif), and Vincent Michael Patella, OD (Carl Zeiss Ophthalmic Systems Inc,Dublin, Calif).

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PubMed
Otteson  DCCirenza  PFHitchcock  PF Persistent neurogenesis in the teleost retina: evidence for regulationby the growth-hormone/insulin-like growth factor-I axis. Mech Dev. 2002;117137- 149
PubMed
Wein  FBLevin  LA Current understanding of neuroprotection in glaucoma. Curr Opin Ophthalmol. 2002;1361- 67
PubMed
Kilpatrick  GJTilbrook  GS Memantine: Merz. Curr Opin Investig Drugs. 2002;3798- 806
PubMed
Schori  HKipnis  JYoles  E  et al.  Vaccination for protection of retinal ganglion cells against deathfrom glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci U S A. 2001;983398- 3403
PubMed
Flammer  JOrgul  SCosta  VP  et al.  The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21359- 393
PubMed
Alvarado  JMurphy  CJuster  R Trabecular meshwork cellularity in primary open-angle glaucoma andnonglaucomatous normals. Ophthalmology. 1984;91564- 579
PubMed
Hernandez  MRAndrzejewska  WMNeufeld  AH Changes in the extracellular matrix of the human optic nerve head inprimary open-angle glaucoma. Am J Ophthalmol. 1990;109180- 188
PubMed
Neufeld  AHHernandez  MRGonzalez  M Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997;115497- 503
PubMed
Pena  JDAgapova  OGabelt  BT  et al.  Increased elastin expression in astrocytes of the lamina cribrosa inresponse to elevated intraocular pressure. Invest Ophthalmol Vis Sci. 2001;422303- 2314
PubMed
Frade  JMBovolenta  PRodriguez-Tebar  A Neurotrophins and other growth factors in the generation of retinalneurons. Microsc Res Tech. 1999;45243- 251
PubMed
Stuermer  CABastmeyer  M The retinal axon's pathfinding to the optic disk. Prog Neurobiol. 2000;62197- 214
PubMed
Mason  CASretavan  DW Glia, neurons, and axon pathfinding during optic chiasm development. Curr Opin Neurobiol. 1997;7647- 653
PubMed
MacLaren  RE Regeneration and transplantation of the optic nerve: developing a clinicalstrategy. Br J Ophthalmol. 1998;82577- 583
PubMed
Fricker  RACarpenter  MKWinkler  CGreco  CGates  MABjorklund  A Site-specific migration and neuronal differentiation of human neuralprogenitor cells after transplantation in the adult rat brain. J Neurosci. 1999;195990- 6005
PubMed
Chang  ATourtellotte  WWRudick  RTrapp  BD Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002;346165- 173
PubMed
Niehaus  AShi  JGrzenkowski  M  et al.  Patients with active relapsing-remitting multiple sclerosis synthesizeantibodies recognizing oligodendrocyte progenitor cell surface protein: implicationsfor remyelination. Ann Neurol. 2000;48362- 371
PubMed
Lucchinetti  CBruck  WParisi  JScheithauer  BRodriguez  MLassmann  H Heterogeneity of multiple sclerosis lesions: implications for the pathogenesisof demyelination. Ann Neurol. 2000;47707- 717
PubMed

Figures

Tables

References

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Xie  TSpradling  AC A niche maintaining germ line stem cells in the Drosophila ovary. Science. 2000;290328- 330
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Raymond  PAHitchcock  PF How the neural retina regenerates. Results Probl Cell Differ. 2000;31197- 218
PubMed
Boucher  SEHitchcock  PF Insulin-related growth factors stimulate proliferation of retinal progenitorsin the goldfish. J Comp Neurol. 1998;394386- 394
PubMed
Otteson  DCCirenza  PFHitchcock  PF Persistent neurogenesis in the teleost retina: evidence for regulationby the growth-hormone/insulin-like growth factor-I axis. Mech Dev. 2002;117137- 149
PubMed
Wein  FBLevin  LA Current understanding of neuroprotection in glaucoma. Curr Opin Ophthalmol. 2002;1361- 67
PubMed
Kilpatrick  GJTilbrook  GS Memantine: Merz. Curr Opin Investig Drugs. 2002;3798- 806
PubMed
Schori  HKipnis  JYoles  E  et al.  Vaccination for protection of retinal ganglion cells against deathfrom glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci U S A. 2001;983398- 3403
PubMed
Flammer  JOrgul  SCosta  VP  et al.  The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21359- 393
PubMed
Alvarado  JMurphy  CJuster  R Trabecular meshwork cellularity in primary open-angle glaucoma andnonglaucomatous normals. Ophthalmology. 1984;91564- 579
PubMed
Hernandez  MRAndrzejewska  WMNeufeld  AH Changes in the extracellular matrix of the human optic nerve head inprimary open-angle glaucoma. Am J Ophthalmol. 1990;109180- 188
PubMed
Neufeld  AHHernandez  MRGonzalez  M Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997;115497- 503
PubMed
Pena  JDAgapova  OGabelt  BT  et al.  Increased elastin expression in astrocytes of the lamina cribrosa inresponse to elevated intraocular pressure. Invest Ophthalmol Vis Sci. 2001;422303- 2314
PubMed
Frade  JMBovolenta  PRodriguez-Tebar  A Neurotrophins and other growth factors in the generation of retinalneurons. Microsc Res Tech. 1999;45243- 251
PubMed
Stuermer  CABastmeyer  M The retinal axon's pathfinding to the optic disk. Prog Neurobiol. 2000;62197- 214
PubMed
Mason  CASretavan  DW Glia, neurons, and axon pathfinding during optic chiasm development. Curr Opin Neurobiol. 1997;7647- 653
PubMed
MacLaren  RE Regeneration and transplantation of the optic nerve: developing a clinicalstrategy. Br J Ophthalmol. 1998;82577- 583
PubMed
Fricker  RACarpenter  MKWinkler  CGreco  CGates  MABjorklund  A Site-specific migration and neuronal differentiation of human neuralprogenitor cells after transplantation in the adult rat brain. J Neurosci. 1999;195990- 6005
PubMed
Chang  ATourtellotte  WWRudick  RTrapp  BD Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002;346165- 173
PubMed
Niehaus  AShi  JGrzenkowski  M  et al.  Patients with active relapsing-remitting multiple sclerosis synthesizeantibodies recognizing oligodendrocyte progenitor cell surface protein: implicationsfor remyelination. Ann Neurol. 2000;48362- 371
PubMed
Lucchinetti  CBruck  WParisi  JScheithauer  BRodriguez  MLassmann  H Heterogeneity of multiple sclerosis lesions: implications for the pathogenesisof demyelination. Ann Neurol. 2000;47707- 717
PubMed

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